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1
Basden, K., DW Cooper, and EM Deane. "Development of the blood-forming tissues of the tammar wallaby Macropus eugenii." Reproduction, Fertility and Development 8, no. 6 (1996): 989. http://dx.doi.org/10.1071/rd9960989.
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The development of the haematopoietic tissues of the tammar wallaby Macropus eugenii follows a similar pattern to that observed in eutherian and other metatherian mammals. At birth, the liver appears to be the only site of haematopoiesis with significant numbers of neutrophils and stem cells present in the circulation. By Day 3, the spleen shows limited haematopoietic activity and by Day 12 contains areas of erythroid and myeloid cells. At two weeks after birth, the haematopoetic activity in the liver declines and small areas of haematopoiesis are apparent in the bone marrow. By the end of the first month, the bone marrow appears to be the major site of haematopoiesis.
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Haznedaroglu, Ibrahim C., and Yavuz Beyazit. "Local bone marrow renin–angiotensin system in primitive, definitive and neoplastic haematopoiesis." Clinical Science 124, no. 5 (November 12, 2012): 307–23. http://dx.doi.org/10.1042/cs20120300.
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The locally active ligand peptides, mediators, receptors and signalling pathways of the haematopoietic BM (bone marrow) autocrine/paracrine RAS (renin–angiotensin system) affect the essential steps of definitive blood cell production. Haematopoiesis, erythropoiesis, myelopoiesis, formation of monocytic and lymphocytic lineages, thrombopoiesis and other stromal cellular elements are regulated by the local BM RAS. The local BM RAS is present and active even in primitive embryonic haematopoiesis. ACE (angiotensin-converting enzyme) is expressed on the surface of the first endothelial and haematopoietic cells, forming the marrow cavity in the embryo. ACE marks early haematopoietic precursor cells and long-term blood-forming CD34+ BM cells. The local autocrine tissue BM RAS may also be active in neoplastic haematopoiesis. Critical RAS mediators such as renin, ACE, AngII (angiotensin II) and angiotensinogen have been identified in leukaemic blast cells. The local tissue RAS influences tumour growth and metastases in an autocrine and paracrine fashion via the modulation of numerous carcinogenic events, such as angiogenesis, apoptosis, cellular proliferation, immune responses, cell signalling and extracellular matrix formation. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive, definitive and neoplastic haematopoiesis. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of neoplastic disorders.
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Al-Drees, Mohammad A., Jia Hao Yeo, Badwi B. Boumelhem, Veronica I. Antas, Kurt W. L. Brigden, Chanukya K. Colonne, and Stuart T. Fraser. "Making Blood: The Haematopoietic Niche throughout Ontogeny." Stem Cells International 2015 (2015): 1–14. http://dx.doi.org/10.1155/2015/571893.
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Approximately one-quarter of all cells in the adult human body are blood cells. The haematopoietic system is therefore massive in scale and requires exquisite regulation to be maintained under homeostatic conditions. It must also be able to respond when needed, such as during infection or following blood loss, to produce more blood cells. Supporting cells serve to maintain haematopoietic stem and progenitor cells during homeostatic and pathological conditions. This coalition of supportive cell types, organised in specific tissues, is termed the haematopoietic niche. Haematopoietic stem and progenitor cells are generated in a number of distinct locations during mammalian embryogenesis. These stem and progenitor cells migrate to a variety of anatomical locations through the conceptus until finally homing to the bone marrow shortly before birth. Under stress, extramedullary haematopoiesis can take place in regions that are typically lacking in blood-producing activity. Our aim in this review is to examine blood production throughout the embryo and adult, under normal and pathological conditions, to identify commonalities and distinctions between each niche. A clearer understanding of the mechanism underlying each haematopoietic niche can be applied to improvingex vivocultures of haematopoietic stem cells and potentially lead to new directions for transplantation medicine.
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Sanchez-Herrero, Alvaro, Isabel A. Calvo, Maria Flandes-Iparraguirre, Marietta Landgraf, Christoph A. Lahr, Abbas Shafiee, Froilán Granero-Molto, et al. "Engineering a Humanised Niche to Support Human Haematopoiesis in Mice: Novel Opportunities in Modelling Cancer." Cancers 12, no. 8 (August 6, 2020): 2205. http://dx.doi.org/10.3390/cancers12082205.
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Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the combination of an orthotopic humanised tissue-engineered bone construct (ohTEBC) with patient-specific bone marrow (BM) cells to create a humanised bone marrow (hBM) niche capable of supporting the engraftment of human haematopoietic cells. Results showed that this model supports the engraftment of human CD34+ cells from a healthy BM with human haematopoietic cells migrating into the mouse BM, human BM compartment, spleen and peripheral blood. We compared these results with the engraftment capacity of human CD34+ cells obtained from patients with multiple myeloma (MM). We demonstrated that CD34+ cells derived from a diseased BM had a reduced engraftment potential compared to healthy patients and that a higher cell dose is required to achieve engraftment of human haematopoietic cells in peripheral blood. Finally, we observed that hematopoietic cells obtained from the mobilised peripheral blood of patients yields a higher number of CD34+, overcoming this problem. In conclusion, this humanised mouse model has potential as a unique and patient-specific pre-clinical platform for the study of tumour–microenvironment interactions, including human bone and haematopoietic cells, and could, in the future, serve as a drug testing platform.
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Pirillo, Chiara, Myriam Haltalli, Sara Gonzalez-anton, George Adams, Delfim Duarte, and Cristina Lo Celso. "Inhibiting Matrix Metalloproteinases Hinders Acute Myeloid Leukaemia and Prevents Healthy Stem Cell Loss." Blood 134, Supplement_1 (November 13, 2019): 2487. http://dx.doi.org/10.1182/blood-2019-129847.
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Haematopoietic stem cells (HSCs), despite being very rare (<0.015% of bone marrow haematopoietic cells), maintain the turnover of all blood cells through a balance of quiescence, self-renewal and differentiation. Disruption of HSCs function and of the bone marrow (BM) microenvironment are key aspects of Acute Myeloid Leukaemia (AML). AML develops in adults and symptoms arise due to the loss of healthy haematopoietic cells. It is unknown exactly what factors contribute to this although it is clear that there is a progressive loss of BM HSCs in this disease. One hypothesis is that HSCs are pushed out of the BM niche by competing leukaemic blasts. To explore this, we used intravital 2-photon confocal microscopy in a live mouse model of leukaemia which allows us to visualise the dynamics of healthy haematopoietc cells at various stages of the disease. We monitored the development of extramedullary haematopoiesis (EMH) during AML growth and tested the function of HSCs found in these alternative sites to determine whether EMH acts as an alternative mechanism of blood cell maintenance in response to AML. Furthermore, we investigated the influence of an extracellular matrix metalloproteinase inhibitor, Prinomastat, on the loss of HSCs in this model. Prinomastat has been studied extensively in solid organ cancers as it has been shown capable of inhibiting cancer metastasis. In this study, we examined whether it might have a function in preventing the loss of HSCs from the bone during leukaemia infiltration. C57BL/6 mice were injected with 100k of YFP-AML blasts and peripheral blood (PB) checked every four days for AML progression. Cellular dynamics were assessed by intravital microscopy (IVM) of the mouse calvarium and spleen at early (10%), medium (25%) and late (>25%) PB infiltration. To calculate the number of circulating HSCs and progenitors (HSPCs) blood was taken by cardiac puncture and analysed by flow cytometry for HSCPs absolute number. The same was done for BM, spleen and liver HSPCs. HSC functionality was determined by transplanting sorted Lin- c-Kit+ Sca-1+ CD48- CD150+ (LKS Slam) cells from CD45.1 BM, spleen and liver of AML-burdened mice into lethally irradiated C57BL/6 mice. BM reconstitution was then analysed every four weeks. To analyse the role of extracellular matrix remodelling, C57BL/6 mice were transplanted with 100k AML cells tagged with yellow-fluorescent-protein (YFP) and then administered intravenous prinomastat daily. These mice were imaged and had bone marrow analysed using flow cytometry together with a control group at early, medium and late AML based on PB infiltration. AML progression leads to a dramatic and progressive loss HSCPs in the BM. Intravital imaging showed an enhanced egress of healthy cells from the BM into the circulation. Conversely, we found a clear association between the extent of infiltration of the marrow and the number of HSCs found in the spleen and liver. Our transplantation experiments show that the extramedullary HSCs are functional and able to reconstitute the BM of lethally irradiated mice irrespective of the organ from which they were sorted. Treatment with prinomastat significantly reduced the number of HSCs and progenitors leaving the bone marrow (P=0.0001). In the treated mice, the number of BM HSCs was consistently higher at every infiltration time point when compared to untreated mice. In addition, prinomastat caused a reduction in the extent of extramedullary haematopoesis in both the spleen and liver. This study provides a unique insight into the effect of AML on the dynamics of HSCs as disease progresses. Contrary to expectations, HSCs are not lost, but rather a majority appear to migrate from the bone marrow to sites of extramedullary haematopoiesis. These cells remain functional and are capable of regenerating haematopoiesis when transplanted into a recipient mouse. Further to this, we have demonstrated that by inhibiting the function of metalloproteinases using Prinomastat it is possible to prevent this loss of HSCs thus retain these cells within the bone marrow. These findings highlight the importance of the extracellular matrix in acute myeloid leukaemia and suggest that metalloproteinase inhibitors could potentially have a significant role in resisting the perturbations caused by AML on haematopoiesis. Disclosures No relevant conflicts of interest to declare.
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Denizot, Y., V. Desplat, C. Dulery, F. Trimoreau, and V. Praloran. "Arachidonic Acid and Freshly Isolated Human Bone Marrow Mononuclear Cells." Mediators of Inflammation 8, no. 1 (1999): 31–35. http://dx.doi.org/10.1080/09629359990694.
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Arachidonic acid (AA), a fatty acid found in the human bone marrow plasma, is the precursor of eicosanoids that modulate bone marrow haematopoiesis. To further our understanding of the role of AA in the bone marrow physiology, we have assessed its incorporation in human bone marrow mononuclear cells. Gas chromatography analysis indicates the presence of AA in their fatty acid composition. In bone marrow mononuclear cells, [3H]-AA is incorporated into triglycerides and is later delivered into phospholipids, a result not observed with blood mononuclear cells. Prelabelling-chase experiments indicate a trafficking of labelled AA from phosphatidylcholine to phosphatidylethanolamine. Stimulation of prelabelled bone marrow mononuclear cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) results in the release of a part of the incorporated labelled AA. Finally, exogenous AA (up to 1 μM) has no significant effect on cell growth. In conclusion, human bone marrow mononuclear cells participate to the control of marrow AA concentrations by incorporating AA into phospholipids and triglycerides. In turn, bone marrow mononuclear cells can release AA in response to the potent haematopoietic growth factor GM-CSF.
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Cuvertino, Sara, Georges Lacaud, and Valerie Kouskoff. "SOX7-enforced expression promotes the expansion of adult blood progenitors and blocks B-cell development." Open Biology 6, no. 7 (July 2016): 160070. http://dx.doi.org/10.1098/rsob.160070.
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During embryogenesis, the three SOXF transcription factors, SOX7, SOX17 and SOX18, regulate the specification of the cardiovascular system and are also involved in the development of haematopoiesis. The ectopic expression of SOX17 in both embryonic and adult blood cells enhances self-renewal. Likewise, the enforced expression of SOX7 during embryonic development promotes the proliferation of early blood progenitors and blocks lineage commitment. However, whether SOX7 expression can also affect the self-renewal of adult blood progenitors has never been explored. In this study, we demonstrate using an inducible transgenic mouse model that the enforced expression of Sox7 ex vivo in bone marrow/stroma cell co-culture promotes the proliferation of blood progenitors which retain multi-lineage short-term engrafting capacity. Furthermore, SOX7 expression induces a profound block in the generation of B lymphocytes. Correspondingly, the ectopic expression of SOX7 in vivo results in dramatic alterations of the haematopoietic system, inducing the proliferation of blood progenitors in the bone marrow while blocking B lymphopoiesis. In addition, SOX7 expression induces extra-medullary haematopoiesis in the spleen and liver. Together, these data demonstrate that the uncontrolled expression of the transcription factor SOX7 in adult haematopoietic cells has dramatic consequences on blood homeostasis.
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Manesso, Erica, José Teles, David Bryder, and Carsten Peterson. "Dynamical modelling of haematopoiesis: an integrated view over the system in homeostasis and under perturbation." Journal of The Royal Society Interface 10, no. 80 (March 6, 2013): 20120817. http://dx.doi.org/10.1098/rsif.2012.0817.
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A very high number of different types of blood cells must be generated daily through a process called haematopoiesis in order to meet the physiological requirements of the organism. All blood cells originate from a population of relatively few haematopoietic stem cells residing in the bone marrow, which give rise to specific progenitors through different lineages. Steady-state dynamics are governed by cell division and commitment rates as well as by population sizes, while feedback components guarantee the restoration of steady-state conditions. In this study, all parameters governing these processes were estimated in a computational model to describe the haematopoietic hierarchy in adult mice. The model consisted of ordinary differential equations and included negative feedback regulation. A combination of literature data, a novel divide et impera approach for steady-state calculations and stochastic optimization allowed one to reduce possible configurations of the system. The model was able to recapitulate the fundamental steady-state features of haematopoiesis and simulate the re-establishment of steady-state conditions after haemorrhage and bone marrow transplantation. This computational approach to the haematopoietic system is novel and provides insight into the dynamics and the nature of possible solutions, with potential applications in both fundamental and clinical research.
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Ramasamy, Saravana K. "Structure and Functions of Blood Vessels and Vascular Niches in Bone." Stem Cells International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/5046953.
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Bone provides nurturing microenvironments for an array of cell types that coordinate important physiological functions of the skeleton, such as energy metabolism, mineral homeostasis, osteogenesis, and haematopoiesis. Endothelial cells form an intricate network of blood vessels that organises and sustains various microenvironments in bone. The recent identification of heterogeneity in the bone vasculature supports the existence of multiple vascular niches within the bone marrow compartment. A unique combination of cells and factors defining a particular microenvironment, supply regulatory signals to mediate a specific function. This review discusses recent developments in our understanding of vascular niches in bone that play a critical role in regulating the behaviour of multipotent haematopoietic and mesenchymal stem cells during development and homeostasis.
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Fouillard, Loic, Alain Chapel, Domnique Bories, Sandrine Bouchet Tec, Helene Rouard, Patrick Herve, Patrick Gourmelon, Dominique Thierry, and Norbert C. Gorin. "Allogeneic Related HLA Mismatch Mesenchymal Stem Cells for the Treatment of Engraftment Failure Following Autologous Hematopoietic Stem Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 2560. http://dx.doi.org/10.1182/blood.v108.11.2560.2560.
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Abstract Primary graft failure is usually associated with a high mortality rate despite infusion of back up graft and haematopoietic growth factors. In animal models mesenchymal stem cells (MSC) stimulate haematopoiesis recovery after TBI and enhance engraftment of haematopoietic stem cells (Almeida-Porada et al, Exp hematol 1999). Co-infusion of autologous blood stem cells and MSC in cancer patients receiving high dose chemotherapy speed up haematopoietic recovery (Koç et al, JCO 2000). We have previously shown that MSC can engraft and improve the bone marrow microenvironment in a patient with end stage severe aplastic anaemia (Fouillard et al, Leukemia 2003). We report a patient treated with MSC for aplastic anemia secondary to engraftment failure. A 40 year old nulliparous woman with acute myeloid leukaemia received an autologous bone marrow transplantation; conditioning regimen combined a 12 Gray TBI and cyclophosphamide (120 mg/kg). Primary graft failure occurred and persited despite back up marrow infusion. Partial recovery on polymorphonuclear (PMN) and haemoglobin (Hb) was obtained with granulocyte colony stimulating factor (G-CSF) and EPO. Thrombocytopenia remained below 50x109/l. No residual leukaemic cells were detected Three years after ABMT, allogeneic MSC were infused at a dose of 2,78x106/kg. MSC were isolated from a HLA mismatched brother bone marrow (Osiris Therapeutics Inc Baltimore, MD). At time of MSC infusion, the marrow aspirate was hypocellular with no leukaemic blast cells. Blood cell counts were: PMN: 0.8x109/l, platelets: 45x109/l and Hb: 10.5 g/dl. No conditioning regimen and no prophylaxis of GVHD was given. Growth factors were discontinued. After MSC infusion, a rapid haematopoietic recovery was observed on both PMN and platelet which reached a normal level. With a follow up of 18 months, the patient is alive and well. Recovery of haematopoiesis was corroborated by an improvement of in vitro haematopoietic and stromal clonogenic assays. CFU-GM and CFU-F studied the day before MSC infusion, one month and one year after MSC infusion, increased strikingly (p<0.05). LTC-IC increased significantly one year after MSC infusion (p<0.05). There was no change in BFUE. To further characterize the effects seen on haematopoiesis, we utilized a custom RayBiotech antibody array and compared proteins secreted by MSC of recipient before and one year after infusion. This array evidenced an increased secretion of proteins implied in haematopoiesis (Flt3l, GM-CSF, G-CSF, IL1, IL6, TPO, SDF1) one year after MSC infusion. Real time PCR confirmed an up-regulation of gene expression for GCSF, GM-CSF, IL1, IL6. We studied MSC engraftment. We analysed the bone marrow biopsy extracted DNA for mesenchymal chimerism before MSC infusion, one month and one year post MSC infusion by real time quantitative PCR of the Y specific SRY gene: male DNA was not detected before infusion; a level of male DNA of 1/105 was detected one month after MSC infusion. This observation shows that MSC can induce haematopoietic tissue repair. MSC should be considered in the treatment of engraftment failure and other bone marrow failure states including severe idiopathic aplastic anaemia and accidental irradiation.
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Lo Celso, Cristina, Edwin D. Hawkins, Delfim Duarte, Olufolake Akinduro, Reema A. Khorshed, Diana Passaro, Malgorzata Nowicka, et al. "Intravital Microscopy Reveals Fundamental Differences in the Interaction of Stem Cells and T Acute Lymphoblastic Leukaemia with the Bone Marrow Microenvironment." Blood 128, no. 22 (December 2, 2016): 5199. http://dx.doi.org/10.1182/blood.v128.22.5199.5199.
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Abstract Haematopoiesis is the complex developmental process maintaining the turnover of all blood cell lineages, i.e. erythrocytes, immune (white) cells and platelets. It takes place primarily in the bone marrow, where it critically depends on the correct functioning of rare, quiescent haematopoietic stem cells (HSCs) and more numerous HSC-derived, highly proliferative and differentiating haematopoietic progenitor cells (HPCs). This is regulated by complex interactions between stem cells and the bone marrow microenvironment, and it was suggested to change in settings involving stress. Indeed, using intravital microscopy, we previously showed that HSCs injected in irradiated recipients steadily engage with endosteal niches. Moreover, if phenotypically identical HSCs are harvested from mice harbouring a natural infection, such as that caused by T.spiralis, they show a unique 'stop and go' migratory behaviour, engage larger niches, yet remain in the proximity of osteoblastic cells. Based on these and other studies, it has been hypothesised that also malignant haematopoietic cells rely on interactions with specific bone marrow microenvironments to grow, and especially to develop chemoresistance. To investigate this further, we performed longitudinal imaging of mice injected with murine and human T acute lymphoblastic leukaemia (T-ALL) cells over the course of hours or days, including during response to multiple chemotherapy treatments. Strikingly, we observed a very different behaviour from that of HSCs, with T-ALL cells showing a highly migratory behaviour throughout all stages of disease, from initial bone marrow infiltration to response to chemotherapy. Interestingly, in untreated mice and in patients trephine biopsies we observed rapid loss of osteoblastic cells by apoptosis, an event that likely contributes to the dramatic loss of healthy haematopoiesis observed in mice and patients. Together, these finds indicate that novel therapeutic strategies should target the ability of T-ALL cells to entertain short-lived and promiscuous interactions with any neighbouring cells, and aim to strengthen the bone marrow microenvironment to improve support for residual healthy haematopoiesis. Disclosures Harrison: AbbVie: Research Funding; Janssen Cilag: Research Funding, Speakers Bureau. Quach:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
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Sanchez, M., B. Gottgens, A. M. Sinclair, M. Stanley, C. G. Begley, S. Hunter, and A. R. Green. "An SCL 3′ enhancer targets developing endothelium together with embryonic and adult haematopoietic progenitors." Development 126, no. 17 (September 1, 1999): 3891–904. http://dx.doi.org/10.1242/dev.126.17.3891.
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The SCL gene encodes a basic helix-loop-helix transcription factor which is expressed in early haematopoietic progenitors throughout ontogeny and is essential for the normal development of blood and blood vessels. Transgenic studies have characterised spatially distinct 5′ enhancers which direct lacZ expression to subdomains of the normal SCL expression pattern, but the same elements failed to produce appropriate haematopoietic expression. We now describe an SCL 3′ enhancer with unique properties. It directed lacZ expression in transgenic mice to extra-embryonic mesoderm and subsequently to both endothelial cells and to a subset of blood cells at multiple sites of embryonic haematopoiesis including the yolk sac, para-aortic splanchnopleura and AGM region. The 3′ enhancer also targeted expression to haematopoietic progenitors in both foetal liver and adult bone marrow. Purified lacZ(+)cells were highly enriched for clonogenic myeloid and erythroid progenitors as well as day-12 spleen colony forming units (CFU-S). Within the total gated population from bone marrow, 95% of the myeloid and 90% of the erythroid colony-forming cells were contained in the lacZ(+) fraction, as were 98% of the CFU-S. Activation of the enhancer did not require SCL protein. On the contrary, transgene expression in yolk sacs was markedly increased in an SCL−/− background, suggesting that SCL is subject to negative autoregulation. Alternatively the SCL−/− environment may alter differentiation of extra-embryonic mesoderm and result in an increased number of cells capable of expressing high levels of the transgene. Our data represents the first description of an enhancer that integrates information necessary for expression in developing endothelium and early haematopoietic progenitors at distinct times and sites throughout ontogeny. This enhancer provides a potent tool for the manipulation of haematopoiesis and vasculogenesis in vivo.
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Uddin, Mohammed Mosleh, Huque Mahfuz, and Md Mostafil Karim. "Beginning of a Journey of Autologous Stem Cell Transplantation in Combined Military Hospital, Dhaka, Bangladesh." BIRDEM Medical Journal 8, no. 2 (May 16, 2018): 177–80. http://dx.doi.org/10.3329/birdem.v8i2.36651.
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Haematopoietic stem cell transplantation (HSCT) involves the intravenous infusion of autologous or allogenic stem cells collected from bone marrow, peripheral blood or umbilical cord to re-establish haematopoietic function in patients whose bone marrow or immune system is damaged or defective. HSCT are mainly of two types –autologous stem cell transplantation (SCT) and allogenic SCT. Autologous SCT is mainly performed in multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma and less commonly in acute myeloid leukaemia. Haematopoietic stem cells are mobilized from bone marrow to the peripheral blood after the use of mobilizing agents, granulocyte colony stimulating factor (G-CSF) and plerixafor. Then the mobilized stem cells are collected from peripheral blood by apheresis and cryo-preserved. The patient is prepared by giving conditioning regimen (high dose melphelan). Stem cells, which are already collected, are re-infused into patient’s circulation by a blood transfusion set. Engraftment happens 7-14 days after auto SCT. Common side effects of this procedure include nausea, vomiting, diarrhoea, mucositis, infections etc. The first case of SCT performed in Combined Military Hospital, Dhaka, Bangladesh is presented here.Birdem Med J 2018; 8(2): 177-180
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Rosskopf, K., S. J. Ragg, N. Worel, M. Grommé, F. W. M. B. Preijers, E. Braakman, G. J. Schuurhuis, et al. "Quality controls of cryopreserved haematopoietic progenitor cells (peripheral blood, cord blood, bone marrow)." Vox Sanguinis 101, no. 3 (September 16, 2011): 255–75. http://dx.doi.org/10.1111/j.1423-0410.2011.01471.x.
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Balsam, Leora B., and Robert C. Robbins. "Haematopoietic stem cells and repair of the ischaemic heart." Clinical Science 109, no. 6 (November 23, 2005): 483–92. http://dx.doi.org/10.1042/cs20050087.
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HSCs (haematopoietic stem cells) are multipotent stem cells that give rise to all cells of the blood cell lineage. In recent years, it has been proposed that bone marrow serves as a reservoir for cardiomyogenic precursors and that, following cardiac injury, these stem cells circulate to the site of injury where they contribute to myocardial repair and regeneration. This concept of stem cell plasticity has been controversial and, in fact, several key studies on the cardiomyogenic potential of HSCs have not been reproducible in the hands of independent investigators. Despite this controversy, the clinical community has pushed forward with clinical trials of bone marrow transplantation for the treatment of ischaemic heart disease. The following review summarizes the mechanistic underpinnings of bone marrow transplantation into ischaemic myocardium, focusing on the basic science that forms the foundation of this field, and highlights the controversies and new avenues for research that have emerged. It also describes the current state of the art in clinical trials of bone marrow transplantation for heart failure.
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Mehta, Milan M., Timothy S. Kemp, and Faddy Hardo. "Acute Leukaemia." InnovAiT: Education and inspiration for general practice 2, no. 8 (July 20, 2009): 458–65. http://dx.doi.org/10.1093/innovait/inp113.
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A cute leukaemias are malignant disorders that arise from the clonal proliferation of a single haematopoietic stem cell. The morbidity and mortality associated with acute leukaemias are due to the effects of bone marrow failure which arises from the accumulation of abnormal blood cells in the bone marrow.
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Hoeben, R. C., M. P. W. Einerhand, E. Briët, H. van Ormondt, D. Valerio, and A. J. van der Eb. "Toward Gene Therapy in Haemophilia A: Retrovirus-Mediated Transfer of a Factor VIII Gene into Murine Haematopoietic Progenitor Cells." Thrombosis and Haemostasis 67, no. 03 (1992): 341–45. http://dx.doi.org/10.1055/s-0038-1648444.
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SummaryTo study and evaluate the potential of the haematopoietic system as a target for gene therapy in haemophilia A, we have infected murine bone-marrow cells with a recombinant retrovirus encoding blood-coagulation factor VIII and the bacterial enzyme neomycin-phosphotransferase. After transplantation of the infected bone marrow into lethally irradiated mice, the presence of intact vector could be demonstrated in DNA isolated from individual haematopoietic progenitor-cell-derived spleen colonies. About 8% of the spleen colonies were shown to contain the intact vector. Selection for resistance to the neomycin analogue G418 prior to transplantation specifically killed the uninfected bone-marrow cells and, as a result, over 90% of the spleen colonies contained the factor VIII vector. However, expression of factor VIII in vivo, either at the RNA or at the protein level could not be demonstrated. From these data we conclude that: 1) retroviral vectors can be used to transfer factor-VIII cDNA into haematopoietic progenitor cells; 2) the vector sequences are expressed immediately after integration; and 3) transcription of the vector is repressed in the progenitor-cell-derived cells.
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Perkins, Andrew C. "Enrichment of blood from embryonic stem cells in vitro." Reproduction, Fertility and Development 10, no. 8 (1998): 563. http://dx.doi.org/10.1071/rd98104.
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Murine embryonic stem (ES) cells are pluripotent. When injected into blastocysts they can give rise to every cell type of a derived chimeric mouse including germ cells. Embryonic stem cells also possess remarkable in vitro differentiation potential. When removed from stromal support and leukaemia inhibitory factor (LIF), ES cells differentiate into structures known as embryoid bodies (EBs), in which all three germ layers develop and interact. As ES cells from humans become available there is increasing interest in the potential for EBs to provide an unlimited supply of stem cells for somatic transplantation therapies. Realisation of this potential will require greater understanding of the molecular determinants of cell fate within EBs. Also, culture techniques for selective expansion of cell lineages of interest will reduce the risks associated with transplantation of EB-derived cells. In this paper the kinetics of expression of mRNA and protein for early mesoderm markers within EBs is reported. In addition, a three-step culture system incorporating co-cultivation on the bone marrow derived stromal cell line, MC3T3-G2/PA6 (PA6), is explored as a way to select for haematopoietic progenitor cells (HPCs) and against undifferentiated ES cells. A system like this could enhance purification of haematopoietic stem cells (HSCs) from ES cells for bone marrow transplantation.
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Pafumi, Carlo, Vito Leanza, Antonio Carbonaro, Gianluca Leanza, Alessandra Iemmola, Giusi Abate, Maria Grazia Stracquadanio, and Alfio D’Agati. "CD34+ stem cells from umbilical cord blood." Clinics and Practice 1, no. 3 (October 27, 2011): 79. http://dx.doi.org/10.4081/cp.2011.e79.
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We describe the relation between umbilical cord clamping time and two different enrichment system of CD34+ stem cells from umbilical cord blood with the proliferative ability and bone marrow reconstitution of the stem cells obtained. After an obstetrician performed the cord blood collection, the purification of stem cells was performed either with a combination of monoclonal antibodies (negative selections) using the Stem Sep method, or with a positive cells selection based on their surface CD34 antigens using the Mini Macs system. An excellent recovery of haematopoietic progenitors [Burst Forming Unit Erythroids (BFUE); Colony Forming Unit Granulocytes and Macrophages (CFU-GM); and Colony Forming Unit Granulocytes, Erythroids, Monocytes and Macrophages (CFU-GME)], inversely related to the increase in clamping time, was performed with the Mini Macs system (54% of colonies, with 90% purity). With Stem Sep method, haematopoietic progenitor’s recovery was 35% (with 80% purity). By applying early clamping of umbilical cord blood we obtained a greater number of CD34+ cells and their clonogenic activity was increased with enrichment. This is a useful technique considering that the number of CD34+ stem cells usually contained from a unit of placental blood is enough for the transplant to a child, but not for an adult. Thus, using these methods, we can get a larger number of CD34+ stem cells which reduces the risk of Graft versus Host Disease also in adult patients, producing survival rates similar to those obtained with transplantation of bone marrow from unrelated donors.
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Silberstein, Lev, Maria Jose Sanchez, Merav Socolovsky, Gary J. Hoffman, Sandie Piltz, Mark Bowen, Anthony R. Green, and Berthold Gottgens. "An SCL +19 Core Enhancer Targets Three Mesoderm-Derived Cell Lineages - Blood, Endothelium and Smooth Muscle." Blood 104, no. 11 (November 16, 2004): 4200. http://dx.doi.org/10.1182/blood.v104.11.4200.4200.
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Abstract The stem cell leukaemia (SCL) gene encodes a basic helix-loop-helix transcription factor with a critical role in normal haematopoiesis and angiogenesis. The SCL gene is normally expressed in haematopoietic stem cells, mast cells, megakaryocytes, endothelium and smooth muscle. Aberrant expression of the SCL gene leads to T-cell acute lymphoblastic leukaemia, whereas SCL−/− mice die due to the absence of haematopoiesis. Hence, temporal and spatial regulation of SCL expression is essential. Our laboratory has previously characterised a 5.5 kb enhancer located 3′ of the SCL transcription start site, which is capable of targeting expression of b-galactozidase (LacZ) reporter gene to haematopoietic stem cells in the foetal liver and the bone marrow, as well as embryonic endothelium. Subsequent experiments showed that a 641-base pair core enhancer gave an identical pattern of lacZ expression in the embryo. However, it was unclear if the same element (later referred to as +19 core enhancer) was capable of maintaining reporter gene expression into the adulthood, since no lacZ activity was observed in postnatal mice. Using a transgenic construct containing a eukaryotic reporter gene, human placental alkaline phosphatase, we show that in the haematopoietic system, the +19 core enhancer is sufficient to target foetal liver and bone marrow HSCs, as well as mast cells and megakaryocytes. In the erythroid lineage, the enhancer is active only during the earlier stages of erythropoiesis, despite high level of SCL expression throughout erythroblast maturation, suggesting that an additional element is likely to be required to maintain SCL expression. The enhancer also targets embryonic and adult endothelium, together with vascular and visceral smooth muscle. Taken together, our results demonstrate that the 641-bp +19 core enhancer is sufficient to integrate signals upstream of SCL in blood, endothelium and smooth muscle. Our data also suggest that developmental relationship between these three mesoderm-derived lineages could be defined through a common transcriptional environment, and indicate that SCL may play a wider role in mesodermal development than previously thought.
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Yao, Weili, Qi Wen, Hong-Yan Zhao, Yuan-Yuan Zhang, Shuqian Tang, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Xiao Jun Huang, and Yuan Kong. "Different Subsets of Haematopoietic Cells and Immune Cells in Bone Marrow between Young and Old Donors." Blood 136, Supplement 1 (November 5, 2020): 33–34. http://dx.doi.org/10.1182/blood-2020-134758.
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Background Young donors are reported to be associated with better transplant outcomes than old donors in allo-HSCT, but the underlying mechanism is still uncertain. Successful allo-HSCT relies on the rapid reconstitution of donor-derived haematopoietic and immune systems in the recipient. Therefore, characterizing the differences in percentages of HSCs and progenitors and immune cell subtypes between young and old donors may help explain the disparities in transplant outcomes. In humans, HSCs give rise to multipotent progenitors (MPPs) that further segregate into either common myeloid progenitors (CMPs) or multipotent lymphoid progenitors (MLPs), which in turn segregate into either common lymphoid progenitors (CLPs) or granulocyte-macrophage progenitors (GMPs). CMPs further segregate into either megakaryocyte-erythroid progenitor (MEPs), or GMPs. However, differences in the frequencies of HSCs and their progenitors between young and old adults remain uncertain. In addition, aGVHD is generally considered to be associated with increased ratios of donor Th1/Th2, Tc1/Tc2 and M1/M2 macrophage. However, little is known about the cytokine-producing T cell subsets and macrophage subsets in BM between young and old donors. Aims To evaluate the different subsets of HSCs and their progenitors and immune cells among young (aged <30 years), middle-aged (aged 30-45 years), and old donors (aged >45 years). Moreover, to analyze the association between donor characteristics and HSC frequency. M ethods In this prospective study, a total of 60 healthy adult donors, including 20 young donors, 20 middle-aged donors, and 20 old donors were enrolled. The frequencies and ROS levels of BM HSCs(CD34+CD38−CD90+CD45RA−) and progenitors including MPPs(CD34+CD38−CD90−CD45RA−), MLPs(CD34+CD38−CD45RA+), CLPs(CD34+CD38+CD7−CD10+CD45RA+), GMPs(CD34+CD38+CD7−CD10−CD45RA+), CMPs(CD34+CD38+CD7−CD10−CD135+CD45RA+), and MEPs(CD34+CD38+CD7−CD10−CD135−CD45RA−) were quantified by flow cytometry. Furthermore, T cell and macrophage subsets were analyzed in young, middle-aged and old donors by flow cytometry. Effector T cells, naïve T cells, effector memory T cells and central memory T cells were identified as CD45RA+CCR7−, CD45RA+CCR7+, CD45RA−CCR7−, and CD45RA−CCR7+. Th1, Th2, Tc1 and Tc2 were identified as CD3+CD8−IFN-γ+, CD3+CD8−IL-4+, CD3+CD8+IFN-γ+ and CD3+CD8+IL-4+, respectively. In addition, M1 and M2 were identified as CD14+CCR2+CD68+ and CD14+CX3CR1+CD163+. Moreover, the association of donor characteristics with HSC frequency was analysed by univariate and multivariate analysis. Results To determine the differences in HSCs and progenitors in different age donors, HSCs and six subpopulations were compared among young, middle-aged and old donors. The frequencies of HSCs and myeloid progenitors, including CMPs and MEPs in CD34+ cells were significantly lower and the frequencies of lymphoid progenitors including MLPs and CLPs in CD34+ cells were higher in the BM of young donors than in that of old donors. Significantly lower levels of ROS in HSCs and progenitors were observed in young donors than in the other donors. Furthermore, to investigate the differences in the differentiation potential from HSCs to immune cells in different age donors, T cell and macrophage subsets were compared among the three donor age groups. Young donors demonstrated a lower CD4+/CD8+ T cell ratio, lower memory T cell frequency and higher naïve T cell frequency in both CD4+ cells and CD8+ cells. Importantly, BM immune cells from young donors polarized towards less pro-inflammatory T cells characterized by Th1 and Tc1, and more immune suppressor cells, such as M2, than those from old donors. As a result, young donors had lower ratios of Th1/Th2, Tc1/Tc2 and M1/M2 in BM. In addition, multivariate analysis showed that age≥37 was independently correlated with a higher HSC frequency. Conclusion BM HSCs from young donors exhibited a lower frequency, balanced myeloid-lymphoid differentiation potential, lower ROS level and produced more immune suppressors and fewer immune effector cells than those from old donors. Donor age might be a good predictor of HSC frequency. Although further validation is required, the differences in the frequency and immune differentiation potential of HSCs in BM between young and old donors may partly explain the different outcomes of allo-HSCT. Disclosures No relevant conflicts of interest to declare.
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Mangolini, Maurizio, and Ingo Ringshausen. "Bone Marrow Stromal Cells Drive Key Hallmarks of B Cell Malignancies." International Journal of Molecular Sciences 21, no. 4 (February 21, 2020): 1466. http://dx.doi.org/10.3390/ijms21041466.
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All B cell leukaemias and a substantial fraction of lymphomas display a natural niche residency in the bone marrow. While the bone marrow compartment may only be one of several sites of disease manifestations, the strong clinical significance of minimal residual disease (MRD) in the bone marrow strongly suggests that privileged niches exist in this anatomical site favouring central elements of malignant transformation. Here, the co-existence of two hierarchical systems, originating from haematopoietic and mesenchymal stem cells, has extensively been characterised with regard to regulation of the former (blood production) by the latter. How these two systems cooperate under pathological conditions is far less understood and is the focus of many current investigations. More recent single-cell sequencing techniques have now identified an unappreciated cellular heterogeneity of the bone marrow microenvironment. How each of these cell subtypes interact with each other and regulate normal and malignant haematopoiesis remains to be investigated. Here we review the evidences of how bone marrow stroma cells and malignant B cells reciprocally interact. Evidently from published data, these cell–cell interactions induce profound changes in signalling, gene expression and metabolic adaptations. While the past research has largely focussed on understanding changes imposed by stroma- on tumour cells, it is now clear that tumour-cell contact also has fundamental ramifications for the biology of stroma cells. Their careful characterisations are not only interesting from a scientific biological viewpoint but also relevant to clinical practice: Since tumour cells heavily depend on stroma cells for cell survival, proliferation and dissemination, interference with bone marrow stroma–tumour interactions bear therapeutic potential. The molecular characterisation of tumour–stroma interactions can identify new vulnerabilities, which could be therapeutically exploited.
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Bosi, Alberto, and Benedetta Bartolozzi. "Allogeneic Haematopoietic Stem Cell Donation — Current Status with Regard to Safety." European Oncology & Haematology 07, no. 03 (2011): 211. http://dx.doi.org/10.17925/eoh.2011.07.03.211.
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Allogeneic haematopoietic stem cell transplantation (HSCT) represents the first choice of treatment or an important therapeutic option for numerous diseases. Several stem cell sources, such as bone marrow, mobilised peripheral blood stem cells and umbilical cord blood, are suitable for HSCT in clinical practice. However, this procedure is strongly related to availability of a histocompatible donor. In order to increase the probability of finding a histocompatible donor, national and international registries have been developed. Voluntary donation of bone marrow or peripheral blood stem cells for HSCT, both in the related or unrelated setting, is a well-established procedure with an invaluable ethical significance. Even if both procedures are safe, they are not risk free; therefore, the greatest attention has to be paid to the donor and to the donation process through a careful monitoring protocol for donor safety.
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Ema, Hideo, and Hiromitsu Nakauchi. "Bloodlines of haematopoietic stem cell research in Japan." Philosophical Transactions of the Royal Society B: Biological Sciences 363, no. 1500 (March 28, 2008): 2089–97. http://dx.doi.org/10.1098/rstb.2008.2263.
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Haematopoietic stem cells (HSCs) can supply all blood cells throughout the adult life of individuals. Based on this property, HSCs have been used for bone marrow and cord blood transplantation. Among various stem cells, HSCs were recognized earliest and were studied most extensively, providing a model for other stem cells. Knowledge of HSC regulation has rapidly accumulated of late. Contributions of scientists in Japan to progress HSC biology are here briefly overviewed. Focusing on the original work accomplished in Japan in the last two decades, people who have led such activities are introduced and their relationships with one another are sketched.
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Ichim, Christine V., Alden Chesney, Marciano D. Reis, Norman N. Iscove, and Richard A. Wells. "NR2F6, the Mammalian Homologue of Drosophila Seven Up, Can Initiate Myelodysplasia and Acute Leukemia." Blood 110, no. 11 (November 16, 2007): 400. http://dx.doi.org/10.1182/blood.v110.11.400.400.
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Abstract A central conundrum in the biology of myelodysplastic syndrome (MDS) is the observation that haematopoietic cells derived from the MDS clone have an increased disposition to apoptosis, yet gain clonal dominance in the bone marrow (BM). One explanation for this apparent paradox could be that MDS stem cells attain clonal dominance by acquiring an augmented probability of self-renewal. We therefore sought to identify novel genes associated with self-renewal that are overexpressed in both MDS and AML. By analyzing the growth of individual clonal siblings derived from low passage cultures of OCI-AML4 we found the expression of the orphan nuclear receptor NR2F6 to be four-fold higher in leukaemia cells with high proliferative capacity, compared to those which spontaneously lose proliferative ability. NR2F6 mRNA transcripts were more abundant in patients (n=37) with MDS, CMML, and AML compared to normal BM (n=16; p<0.0003 MDS, <0.03 CMML, <0.0009 AML), validating the clinical relevance of this gene and suggesting that deregulation of NR2F6 might be an early event in disease progression. We studied the effects of NR2F6 on differentiation and proliferation in vitro in the monoblastic cell line U937. Induction of differentiation of U937 cells resulted in a decrease in NR2F6 expression, while forced expression of NR2F6 reduced the doubling time of U937 cells, and inhibited induction of differentiation by retinoic acid. We next studied the effects of NR2F6 on the behaviour of primary haematopoietic cells. Overexpression of NR2F6 in murine bone marrow cells resulted in a significant reduction in the number of BFU-E and CFU-GM and the size of erythroid and myeloid colonies, consistent with the idea that NR2F6 inhibits maturation of normal BM. These results were corroborated by immunophenotyping of BM cultured in suspension, which showed that NR2F6 overexpression resulted in a significant reduction in mature monocytes and granulocytes. In addition, serial replating of haematopoietic colonies revealed greatly extended replating potential in NR2F6-overexpressing BM, consistent with augmented self-renewal capacity. Finally, we assessed the effects of NR2F6 on haematopoiesis in vivo by bone marrow transplantation. Competitive repopulation of lethally irradiated murine hosts with NR2F6-transduced bone marrow cells resulted in successful engraftment and augmented self-renewal as evidenced by increased engraftment in some recipients as well as increased colony formation in serial replating experiments. Recipients of NR2F6-transduced grafts had hypercellular BM, with abnormal localization of immature precursors (ALIP) and an increase in the percentage of blasts. Strikingly, ∼30% of recipients of secondary transplants of NR2F6-transduced bone marrow cells developed acute leukaemia, characterized by infiltration by blasts of bone marrow, peripheral blood, spleen and liver, and by haematopoietic failure. These data establish the importance of NR2F6 in the regulation of haematopoietic cell self-renewal and differentiation. This suggests that deregulated expression of NR2F6 is an important step in the pathogenesis of human MDS and AML and supports the hypothesis that acquisition of augmented self-renewal capacity helps the MDS stem cell gain clonal dominance. Furthermore, the NR2F6 transplant chimera system provides a mouse model of MDS, and the transformation of MDS to AML.
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Warnke, Clemens, Vsevolod Smolianov, Thomas Dehmel, Marcel Andrée, Hartmut Hengel, Fabian Zohren, Gabriele Arendt, et al. "CD34+ progenitor cells mobilized by natalizumab are not a relevant reservoir for JC virus." Multiple Sclerosis Journal 17, no. 2 (November 15, 2010): 151–56. http://dx.doi.org/10.1177/1352458510385834.
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Background: Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment in patients with multiple sclerosis (MS). It has been hypothesized that natalizumab mobilizes JC virus (JCV)-infected haematopoietic progenitor cells mediating viraemia and subsequently this disease. Objective: The objective of this study was to investigate peripheral haematopoietic progenitor cells for evidence of JCV DNA in MS patients treated with natalizumab. Methods: We assessed JCV and cytomegalovirus (CMV) DNA in magnetically separated CD34+ haematopoietic progenitor cells, peripheral blood mononuclear cells and plasma of 67 natalizumab-treated patients with MS and six PML patients. Results: Viral DNA was not detectable in CD34+ haematopoietic progenitor or peripheral blood mononuclear cells from any sample. Two plasma samples from patients with MS while undergoing natalizumab treatment were JCV-positive. In one case clinically manifest PML developed 8 months thereafter. Conclusions: Our findings do not support the hypothesis that natalizumab mobilizes JC virus-infected CD34+ cells from the bone marrow mediating JC viraemia. Notably, JC viraemia was detected in one patient with MS prior to developing clinical PML. This warrants further study.
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Essers, Marieke A. G. "Inflammation Mediated Bone Marrow Remodeling." Blood 134, Supplement_1 (November 13, 2019): SCI—2—SCI—2. http://dx.doi.org/10.1182/blood-2019-121050.
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Infection is a common, natural form of stress, with which the body is regularly challenged. During infection or inflammation, cells of the immune system are responsible for fighting the invading pathogens. This leads to consumption of blood and immune cells due to mobilization of these cells to the site of infection, or by apoptosis as part of the host response to invading pathogens. Restoration of the balance of the hematopoietic system following successful elimination of the infection is a crucial part of the recovery of the body. In addition, both clinical and experimental data indicate that depending on the scale and duration, infection and inflammation can induce hematopoietic dysfunction compromising immune defense mechanisms and possibly contributing to the development of hematologic malignancies. Restoring the balance of the hematopoietic system depends on the replacement of lost immune cells by the activity of hematopoietic stem cells (HSCs). During the last ten years we and others could show that this so-called emergency hematopoiesis is driven by pro-inflammatory cytokines, who are increasingly produced upon infection or inflammation in the bone marrow and can directly drive the activation of normally quiescent HSCs. An interesting observation from these data is the often opposing impact of these pro-inflammatory cytokines on HSCs in vivo versus in vitro. Whereas in vivo treatment of mice with for example IFNα leads to a strong increase in proliferation of the HSCs, in vitro treatment with IFNα inhibits the HSCs. Furthermore, data from viral infection experiments have shown sustained alterations in the inflammatory cytokine/chemokine profile in the bone marrow weeks after the infection. All these data suggest that interactions of HSCs with their direct environment or signals from this environment are important for a proper response of the HSCs during environmental stress. Research in recent years has focused on unraveling the different components of the HSC stem cell niche. However, the molecular and cellular basis of the BM HSC niche, and signals exchanged between HSC and niche cells under stress conditions remain poorly understood. We initially focused on how the niche responds to inflammatory stress, and could show that the BM stem cell vascular niche was remodeled in response to IFNα. IFNα treatment of mice resulted in increased BM vascularity, expression of key inflammatory and endothelial-stimulatory markers on ECs and increased BM vascular leakiness. These data indicate a novel acute response of the BM vasculature to primary inflammatory signaling, suggesting alterations of the HSC niche in response to stress. ECs are not the only cells in the BM niche responding to inflammatory stress. Using different mouse models and single cell sequencing technology we are currently not only investigating the impact of inflammatory stress on the other components of the niche but also try to unravel the possible changes in interactions and signals between the HSCs and the niche. One example is our data on the role of the extracellular matrix protein Matrilin-4 (Matn4) in the regulation of the HSC response. Under homeostasis high expression of Matn-4 in HSCs confers a resistance to stress stimuli. In situations of acute stress, such as an infection or transplantation, this protection is rapidly lost through down-regulation of Matn-4, allowing HSCs to efficiently replenish the blood system. Thus, these data indicate an important role for the control of the interactions of HSCs with the extracellular matrix in regulating the HSC stress response in vivo. In summary, investigating the response of the bone marrow niche and the role of stem cell-ECM-niche interactions in controlling the HSC stress response will help us to better understand the shortterm and longterm impact of infection and inflammation on the HSCs and their niche. Potential Articles of Interest: Hirche C, Frenz T, Haas S, et al (2017). Systemic Virus Infections differentially modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo. Cell Reports19: 2345-56Velten L, Haas SF, Raffel S, et al (2017). Human haematopoietic stem cell lineage commitment is a continuous process. Cell Biol.19: 271-281Prendergast AM, Kuck A, van Essen M, et al (2017). IFNa mediated remodeling of endothelial cells in the bone marrow niche. Haematologica,102: 445-453Uckelmann H, Blaszkiewicz S, Nicolae C, et al (2016). Extracellular matrix protein Matrilin-4 regulates stress-induced HSC proliferation via CXCR4. J Exp. Med.213: 1961-1971Haas S, Hansson J, Klimmeck D, et al (2015). Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell17: 422-34 Disclosures No relevant conflicts of interest to declare.
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Wedi, E., S. Müller, M. Neusser, P. H. Vogt, O. Y. Tkachenko, J. Zimmer, D. Smeets, H. W. Michelmann, and P. L. Nayudu. "Detection of cross-sex chimerism in the common marmoset monkey (Callithrix jacchus) in interphase cells using fluorescence in situ hybridisation probes specific for the marmoset X and Y chromosomes." Reproduction, Fertility and Development 29, no. 5 (2017): 913. http://dx.doi.org/10.1071/rd15321.
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Chimerism associated with placental sharing in marmosets has been traditionally analysed using conventional chromosome staining on metaphase spreads or polymerase chain reaction. However, the former technique requires the presence of proliferating cells, whereas the latter may be associated with possible blood cell contamination. Therefore, we aimed to develop a single-cell analysis technique for sexing marmoset cells. We applied fluorescent in situ hybridisation (FISH) to cell nuclei using differentially labelled X and Y chromosome-specific probes. Herein we present the validation of this method in metaphase cells from a marmoset lymphoblastoid cell line, as well as application of the method for evaluation of cross-sex chimerism in interphase blood lymphocytes and haematopoietic bone marrow cells from marmosets of same- and mixed-sex litters. The results show conclusively that haematopoietic cells of bone marrow and leucocytes from blood are cross-sex chimeric when the litter is mixed sex. In addition, single samples of liver and spleen cell suspensions from one individual were tested. Cross-sex chimerism was observed in the spleen but not in liver cells. We conclude that FISH is the method of choice to identify cross-sex chimerism, especially when combined with morphological identification of nuclei of different cell types, which will allow a targeted tissue-specific analysis.
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Ju, Wen, Tiantian Sun, Wenyi Lu, Kailin Xu, Jianlin Qiao, and Lingyu Zeng. "The Role of Macrophages in Bone Marrow Injury and Hematopoietic Reconstitution." Blood 134, Supplement_1 (November 13, 2019): 3729. http://dx.doi.org/10.1182/blood-2019-127802.
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Introduction Successful homing, engrafment and effective hematopoietic recovery after hematopoietic stem cell transplantation (HSCT) are strictly regulated by various hematopoietic microenvironment cells. Increasing evidence shows that macrophages (MФs), one of the most important component niche cells are crucial for the haematopoietic regulation. MФs depletion can enhance hematopoietic stem cell mobilization. Our previous study showed that MФs ameliorate bone marrow inflammatory injury and promote hematopoiesis in mice after allo-HSCT, but its role in syngeneic HSCT and acute bone marrow injury is still unknown. Our aim is to explore the role of macrophages in acute bone marrow injury and hematopoietic reconstitution after isogenic hematopoietic stem cell transplantation and sublethal dose irradiation in vivo. Methods BALB/c male mice at 8-10 weeks were irradiated with 60 Co 7.5 Gy and 3.0 Gy, respectively, and then isogenic hematopoietic stem cell transplantation model and sublethal-dose bone marrow injury model were constructed. The transplantation model mice were randomly divided into total body irradiation group (TBI group), bone marrow cell transplantation group (BMT group), bone marrow cell transplantation + Clodronate Liposomes injection group (BMT+Clod-Lip group), bone marrow cell transplantation + PBS Liposomes injection group ( BMT + PBS-Lip group), and normal control group (Normal group). The sublethal-dose experimental mice were randomly divided into the total body irradiation group (TBI group), the whole body irradiation + Clodronate Liposomes injection group (TBI+Clod-Lip group), the whole body irradiation + PBS Liposomes injection group (TBI+PBS-Lip group), and normal control group (Normal group). Mice in Clod-Lip group were injected with Clodronate Liposomes for several specific times to deplete macrophages until the specimens were obtained. Mice in PBS-Lip group were injected PBS Liposomes as controls.Then, the living conditions and body weight changes of the mice were observed and the survival rates of mice in different experimental groups were recorded. Peripheral blood and bone marrow in each group were collected at the corresponding detection time, blood routine analyzer was used to detect blood routine changes, HE staining was used to observe bone marrow damage, and flow cytometry was used to analyze changes in macrophages, hematopoietic stem/progenitor cells and their subgroups such as myeloid cells, megakaryocytes, and nucleated red blood cells in bone marrow. Results Depletion of bone marrow macrophages could reduce the survival rate of hematopoietic stem cell transplantation mice. The pathological results of bone marrow showed that bone marrow injury were heaviest on the 7th day in all three transplantation groups, and then gradually alleviated. The recovery of the BMT+Clod-Lip group was inferior to that of the BMT+PBS-Lip group and the BMT group at the corresponding time point. Depletion of macrophages increased the percentage of myeloid cells in the bone marrow and the number of white blood cells in the peripheral blood, reduced the total number of bone marrow cells, the proportion of hematopoietic stem cells and megakaryocytes in the bone marrow, and delayed recovery of red blood cells and platelets in peripheral blood; Depletion of bone marrow macrophages could also reduce survival rate of sublethal dose irradiation mice, delayed the repair of pathological damage of bone marrow, and increase the proportion of progenitor cells, CMP, GMP, myeloid cells and the number of peripheral white blood cells ,increase the proportion of hematopoietic stem cell apoptosis, reduce the total number of bone marrow cells, the proportion of hematopoietic stem cells, MEP, megakaryocytes and nucleated red blood cells in the bone marrow, delayed peripheral blood recovery of red blood cells and platelets. Conclusion In the isogenic hematopoietic stem cell transplantation model and the sublethal dose irradiation mouse model, the removal of mouse bone marrow macrophages could affect the survival rate of transplanted mice, aggravate the pathological damage of bone marrow, increase the number of GMP and white blood cells, and reduce the total number of bone marrow cells, the number of hematopoietic stem cells and MEP cells. Macrophage depletion was not conducive to the recovery of peripheral blood red blood cells and platelets. Disclosures No relevant conflicts of interest to declare.
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Gruszka, Alicja, Debora Valli, Cecilia Restelli, and Myriam Alcalay. "Adhesion Deregulation in Acute Myeloid Leukaemia." Cells 8, no. 1 (January 17, 2019): 66. http://dx.doi.org/10.3390/cells8010066.
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Cell adhesion is a process through which cells interact with and attach to neighboring cells or matrix using specialized surface cell adhesion molecules (AMs). Adhesion plays an important role in normal haematopoiesis and in acute myeloid leukaemia (AML). AML blasts express many of the AMs identified on normal haematopoietic precursors. Differential expression of AMs between normal haematopoietic cells and leukaemic blasts has been documented to a variable extent, likely reflecting the heterogeneity of the disease. AMs govern a variety of processes within the bone marrow (BM), such as migration, homing, and quiescence. AML blasts home to the BM, as the AM-mediated interaction with the niche protects them from chemotherapeutic agents. On the contrary, they detach from the niches and move from the BM into the peripheral blood to colonize other sites, i.e., the spleen and liver, possibly in a process that is reminiscent of epithelial-to-mesenchymal-transition in metastatic solid cancers. The expression of AMs has a prognostic impact and there are ongoing efforts to therapeutically target adhesion in the fight against leukaemia.
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Sims, Hannah, David Bloxham, Hannah Creasey, Elaine Bradford, Hongxiang Liu, Penny Wright, Anthony Bench, et al. "Rapid Response of Biallelic BRAF V600E Hairy Cell Leukaemia to Low Dose Vemurafenib." Blood 120, no. 21 (November 16, 2012): 4890. http://dx.doi.org/10.1182/blood.v120.21.4890.4890.
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Abstract Abstract 4890 Following the recent report that identified the V600E BRAF mutation in Hairy Cell Leukaemia (HCL) (Tiacci et al NEJM 2011), we confirmed this finding in 48/48 patients diagnosed with HCL in the Cambridge Haematology Laboratory (Boyd et al BJHaem 2011). One of these patients was found to have a bialleleic V600E BRAF mutation on a bone marrow biopsy taken in 2008. Retrospective molecular analysis of diagnostic material from 1996 confirmed this patient's disease was heterozygous for BRAF V600E at presentation. He initially enjoyed a long period of disease stability following splenectomy and cladribine in 1996/1997. He was retreated with 6 cycles of cladribine in 2008 but within 3 years he relapsed again and was treated with 6 cycles of pentostatin and rituximab completing in 2011. He achieved a partial bone marrow remission with recovery of normal peripheral blood counts, but his disease progressed within 6 months. He became profoundly cytopenic with circulating hairy cells and was platelet/red cell transfusion dependent. He was intolerant of interferon-alpha. Following the recent report of the successful treatment of a single patient with a BRAF inhibitor (Dietrich et al NEJM 2012), our patient was treated with vemurafenib at a continuous dose of 240mg BD. Pretreatment Day -7 bloods confirmed total white cell count 20.0 × 109/L, neutrophils 0.8 × 109/l, haemoglobin 9.5 g/dl (supported) and platelets 11 × 109/l (supported). In the 3 months prior to starting vemurafenib, he had received 14 units of red cells, 9 transfusions of platelets and on-going G-CSF therapy. Baseline MRI of pelvis and femora revealed diffusely abnormal homogenous bone marrow signal with increased T2 fat suppressed (T2fs) signal and decreased T1 signal Treatment was tolerated with no discernable side effects to date and renal and liver function remained normal on therapy. Flow cytometry quantification confirmed a rapid reduction in peripheral blood hairy cells from pre treatment 19 x109/l, to 3 x109/l by day 7 and 0.002 x109/l on day 36. The final platelet transfusion was on day 15 and platelet counts increased to 37 × 109/l by day 29 and 94 × 109/l by day 36. The last red cell transfusion was on Day 22 and on day 36 the patient's haemoglobin was 9.4 g/dl. G-CSF was stopped on day 28. The bone marrow remained inaspirable on day 16, but a trephine biopsy revealed early response with some regeneration of normal haematopoiesis. Bone marrow from Day 36 confirmed ongoing haematopoietic recovery but hairy cells persisted. MRI on day 32 showed development of patchy marrow signal throughout consistent with multifocal recovery of haematopoietic marrow. The patient continues on vemurafenib 240mg BD and follow-up data will be presented. Disclosures: Off Label Use: Oral BRAF inhibitor.
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Kutyna, Monika M., Li Yan A. Wee, Sharon Paton, Dimitrios Cakouros, Agnieszka Arthur, Rakchha Chhetri, Andreas W. Schreiber, et al. "Therapy-Related Myeloid Neoplasm Has a Distinct Pro-Inflammatory Bone Marrow Microenvironment and Delayed DNA Damage Repair." Blood 136, Supplement 1 (November 5, 2020): 37–38. http://dx.doi.org/10.1182/blood-2020-137277.
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Introduction: Therapy-related myeloid neoplasms (t-MN) are associated with extremely poor clinical outcomes in otherwise long-term cancer survivors. t-MN accounts for ~20% of cases of myeloid neoplasms and is expected to rise due to the increased use of chemotherapy/radiotherapy (CT/RT) and improved cancer survivorship. Historically, t-MN was considered a direct consequence of DNA damage induced in normal hematopoietic stem cells (HSC) by DNA damaging cytotoxics. However, these studies have largely ignored the bone marrow (BM) microenvironment and the effects of age and concurrent/previous cancers. Aim: We performed an exhaustive functional study of mesenchymal stromal cells (MSC) obtained from a comparatively large cohort of t-MN patients and carefully selected control populations to evaluate the long-term damage induced by cytotoxic therapy to BM microenvironment and its impact on malignant and normal haematopoiesis. Methods: Four different cohorts were used: (1) t-MN, in which myeloid malignancy occurred after CT/RT for a previous cancer (n=18); (2) patients with multiple cancer and in which a myeloid neoplasm developed following an independent cancer which was not treated with CT/RT (MC-MN; n=10); (3) primary MN (p-MN; n=7) untreated and without any prior cancer or CT/RT; (4) age-matched controls (HC; n=17). Morphology, proliferation, cellular senescence, differentiation potential and γH2AX DNA damage response was performed. Stem/progenitor supportive capacity was assessed by co-culturing haematopoietic stem cells on MSC feeder-layer in long-term culture initiating assay (LTC-IC). Cytokine measurements were performed using 38-plex magnetic bead panel (Millipore) and RNA sequencing libraries were prepared with Illumina TruSeq Total RNA protocol for 150bp paired-end sequencing on a NextSeq500 instrument. Functional enrichment analysis was performed using EnrichR software. Results: MSC cultured from t-MN patients were significantly different from HC, p-MN and MC-MN MSC according to multiple parameters. They exhibited aberrant morphology consisting of large, rounded and less adhesive cells compared to typical spindle-shaped morphology observed with controls. MSC from myeloid neoplasm also showed impaired proliferation, senescence, osteo- and adipogenic differentiation with t-MN MSC showing the greatest differences. DNA repair was dramatically impaired compared to p-MN and HC (Fig.1A). Importantly, these aberrant t-MN MSC were not able to support normal or autologous in vitro long-term haematopoiesis (Fig.1B). The biological characteristic and poor haematopoietic supportive capacity of MSC could be "cell-intrinsic" or driven by an altered paracrine inflammatory microenvironment. Interestingly, several inflammatory cytokines were higher in t-MN compared with marrow interstitial fluid obtained from p-MN patients (Fig.1Ci) and many of these including Fractalkine, IFNα2, IL-7 and G-CSF were also significantly higher in t-MN MSC conditional media (Fig.1Cii). Together, this data suggest that t-MN microenvironment is distinct from p-MN with paracrine production of pro-inflammatory milieu that may contribute to poor HSC supportive capacity. Preliminary whole transcriptome analysis revealed differential gene expression between t-MN and HC (Fig.1Di) and p-MN MSC. Importantly, the deregulated genes play critical role in cell cycle, DNA damage repair, and cellular senescence pathways explaining phenotypical characteristic of t-MN MSC (Fig.1Dii). Moreover CXCL12 expression, a key regulator of haematopoiesis, was significantly lower in t-MN compared to HC (p=0.002) and p-MN MSC (p=0.009), thus explaining poor HSC supportive capacity. The key difference between the p-MN, MC-MN and t-MN is prior exposure to CT/RT. To study this we obtained MSC from two t-MN patients for whom we had samples at the time of their primary cancer, post high-dose chemotherapy and at the time of t-MN. MSC displayed aberrant proliferation and differentiation capacity after high-dose cytotoxic therapy (2 to 4 years prior to developing t-MN) and remained aberrant at t-MN diagnosis (Fig.1E). Conclusions: BM-MSC from t-MN patients are significantly abnormal compared with age-matched controls and typical myeloid neoplasm. Importantly, prior CT/RT leads to long-term irreversible damage to the BM microenvironment which potentially contributes to t-MN pathogenesis. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:Novartis Australia: Research Funding.
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Houben, Amelie Pia, Anja Buchheiser, Murat Aktas, Johannes Fischer, Peter Wernet, and Gesine Koegler. "Age-Related Differences Between Unrestricted Somatic Stem Cells from Cord Blood and Bone Marrow Derived Mesenchymal Stroma Cells." Blood 112, no. 11 (November 16, 2008): 1335. http://dx.doi.org/10.1182/blood.v112.11.1335.1335.
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Abstract During the past years haematopoietic stem cells from unrelated umbilical cord blood have been increasingly used for treatment of leukaemia and genetic diseases. Human cord blood also contains a non-haematopoietic, adherently growing, CD45 negative, Oct4, nanog and Sox2 negative cell population with intrinsic multipotent differentiation potential, described as Unrestricted Somatic Stem Cells (USSC) (Kögler et al. 2004, Kögler et al. 2005, Kögler et al. 2006, Sensken et al. 2007, Liedtke et al. 2007, Liedtke et al.2008, Greschat et al. 2008, Ghodsizad A et al. 2008, Trapp et al. 2008). USSC can be cultivated GMP-grade reaching 1×109 cells in Passage 4–5 (correlating to 26,5 – 28 cumulative population doublings) without losing multipotency. To better understand and characterise USSC, we carried out in vitro studies concerning age-related changes in USSC-lines from human cord blood and in mesenchymal stroma cells derived from human bone marrow (BM-MSC). Telomerase activity and telomeres are involved in cell proliferation as well as the regulation of cell senescence (Lansdorp 2008). In this study 7 USSC-lines and 9 BM-MSC were analyzed for proliferation and senescence at different population doublings (PD). In vitro USSC have a higher proliferation capacity and accordingly a comparably more extended lifespan than BM-MSC. They undergo about 35 to 45 CPD whereas mean level of CPD from BM-MSC reaches 25. Telomere length of 12 USSC, 5 BM-MSC and 5 clonal populations of USSC were calculated after several PD and telomerase activity was measured. Mean terminal restriction fragment’s (TRF’s) length calculated from USSC after 31 CPD averages 9.7 kbp whereas mean telomere length from BM-MSC decreases already after 20 CPD to 7.9 kbp. After 47 CPD in clonal USSC populations mean TRF’s length is 6.1 kbp. Telomerase activity was analysed with RT-PCR and real time PCR. In contrast to previous publications telomerase activity was detected neither in BM-MSC (Parsch et al.) 2003 nor in USSCs (Manca et al. 2008). The percentage of senescent cells after the same number of CPD is significantly higher in BM-MSC than in USSC. About 80% of senescence was observed in BM-MSC but only 10% senescence in USSCs after 26 CPD. Wnt signalling is mandatory for self-renewal, cell proliferation and differentiation of haematopoietic stem cells (Reya et al. 2003). In primitive MSC populations Wnt signalling regulates mesenchymal lineage specification (Etheridge et al. 2004). For analysing the role of Wnt pathway in USSC development quantitative PCR Arrays have been carried out profiling the expression of 84 genes related to Wnt-mediated signal transduction. 8 different USSC populations have been analysed. In all USSCs factors essential for canonical and also non-canonical Wnt-signalling are present. Poor proliferating USSC with high adipogenic differentiation potential show a stronger expression of Wnt-signalling inhibitors like SFRP1, DKK1 and CXXC4. Based on age-related characteristics, USSC from cord blood are a much better source for regeneration compared to their adult MSC counterpart from bone marrow.
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Kluth, Simone Maria, Teja Falk Radke, and Gesine Kögler. "Increased Haematopoietic Supportive Function of USSC from Umbilical Cord Blood Compared to CB MSC and Possible Role of DLK-1." Stem Cells International 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/985285.
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Multipotent stromal cells can be isolated from a variety of different tissues in the body. In contrast to stromal cells from the adult bone marrow (BM) or adipose tissue, cord blood (CB) multipotent stromal cells (MSC) are biologically younger. Since first being described by our group, delta like 1 homologue (DLK-1) was determined as a discriminating factor between the distinct cord blood-derived subpopulations: the unrestricted somatic stromal cells (USSC), which lack adipogenic differentiation capacity, and the BM MSC-like CB MSC. In this study, experiments assessing the haematopoiesis-supporting capacity and molecular biological analyses were conducted and clearly confirmed different properties. Compared to CB MSC, USSC lead to a higher expansion of haematopoietic cells and in addition express significantly higher levels of insulin-like growth factor binding protein 1 (IGFBP1), but lower levels of IGF2. The data presented here also indicate that DLK-1 might not be the sole factor responsible for the inhibition of adipogenic differentiation potential in USSC but nevertheless indicates a biological diversity among cord blood-derived stromal cells.
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Tian, Hong, Yang Xu, Guanghua Chen, Man Qiao, and Wu Depei. "JAK2 Mutation Analysis and Function of Bone Marrow Mesenchymal Stem Cells in Myeloproliferative Neoplasms." Blood 118, no. 21 (November 18, 2011): 5179. http://dx.doi.org/10.1182/blood.v118.21.5179.5179.
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Abstract Abstract 5179 Background: JAK2V617F and JAK2 exon12 mutations in haematopoietic cells were partially responsible for the pathogenesis of myeloproliferative neoplasms (MPN).But it was still unclear whether bone marrow mesenchymal stem cells (BMSCs), the significant component of hemopoiesis microenvironment, were participated in the pathogenesis of MPN. Objective: To study the physiopathology characteristics and analyze JAK2 mutation in BMSCs from MPN patients. Methods: By searched for the JAK2V617F mutation and exon 12 mutation in 135 MPN patients' blood /bone marrow samples, 20 patients with JAK2V617F mutation, 10 patients with JAK2 exon 12 mutation, 5 JAK2-mutation-negetive patients and 10 healthy donors were recruited. The phenotype, mesenchymal differentiation capacity, expression of hematopoietic and immune molecules and JAK2 mutation of isolated bone marrow BMSCs were detected. Results: BMSCs derived from the four groups were found to be similar in morphology, differentiation ability and expression of hematopoietic and immune molecules. Primary study indicated that the isolated BMSCs from patients groups were not able to harbor JAK2 mutation in spite of positive or negative JAK2 mutation in blood /bone marrow samples. Conclusion: BMSCs from MPN patients had similar biological characteristics to healthy donors, and BMSCs were not likely involved in pathogenesis of MPN. Disclosures: No relevant conflicts of interest to declare.
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Yasmin, N., N. Kabir, T. Afrin, S. Ahmed, and K. Khatun. "Umbilical Cord Blood Saving - A Lifeline for a Lifetime." Bangladesh Journal of Obstetrics & Gynaecology 27, no. 2 (October 10, 2016): 79–82. http://dx.doi.org/10.3329/bjog.v27i2.29923.
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Introduction: Umbilical cord blood is blood left over in the placenta and in the umbilical cord after the birth of the baby. Umbilical cord blood saving consists of the collection, processing and cryopreservation of the remaining blood within the umbilicus and placenta following the birth of a child. Within this left over blood, traditionally discarded with the placenta as medical waste, lies a rich source of haematopoietic stem cells same as bone marrow. Cord blood stem cells have advantages over bone marrow in transplants and have been used in more than 30,000 transplants to regenerate healthy blood and immune systems1. Today, stem cell therapies continue to evolve, bringing new hope to patients and their families.Objective: To aware regarding use of stem cells of babys umbilical cord blood in future.Methods: A review of relevant articles and documents and some world standard stem cell banking protocol were undertaken.Conclusion: When these cord blood stem cells are processed and stored, the cells are not only a perfect match for the baby, but it could also provide life saving benefits for siblings and other family members.Bangladesh J Obstet Gynaecol, 2012; Vol. 27(2) : 79-82
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MacLean, Adam L., Cristina Lo Celso, and Michael P. H. Stumpf. "Population dynamics of normal and leukaemia stem cells in the haematopoietic stem cell niche show distinct regimes where leukaemia will be controlled." Journal of The Royal Society Interface 10, no. 81 (April 6, 2013): 20120968. http://dx.doi.org/10.1098/rsif.2012.0968.
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Haematopoietic stem cells (HSCs) are responsible for maintaining immune cells, red blood cells and platelets throughout life. HSCs must be located in their ecological niche (the bone marrow) to function correctly, that is, to regenerate themselves and their progeny; the latter eventually exit the bone marrow and enter circulation. We propose that cells with oncogenic potential—cancer/leukaemia stem cells (LSC)—and their progeny will also occupy this niche. Mathematical models, which describe the dynamics of HSCs, LSCs and their progeny allow investigation into the conditions necessary for defeating a malignant invasion of the niche. Two such models are developed and analysed here. To characterize their behaviour, we use an inferential framework that allows us to study regions in parameter space that give rise to desired behaviour together with an assessment of the robustness of the dynamics. Using this approach, we map out conditions under which HSCs can outcompete LSCs. In therapeutic applications, we clearly want to drive haematopoiesis into such regimes and the current analysis provide some guidance as to how we can identify new therapeutic targets. Our results suggest that maintaining a viable population of HSCs and their progenies in the niche may often already be nearly sufficient to eradicate LSCs from the system.
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Starodub, G. S., N. V. Goryainova, T. P. Perekhrestenko, O. V. Basova, N. M. Tretiak, and A. I. Gordiienko. "KI-67 AS A PROGNOSTIC FACTOR OF MYELODYSPLASTIC SYNDROME." Ukrainian Scientific Medical Youth Journal, no. 2(95) (April 29, 2016): 5–8. http://dx.doi.org/10.32345/usmyj.2(95)().2016.5-8.
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Patients with MDS RAEB II were examined. The decrease in dynamics of intracellular K³-67 protein expression was determined in patients with MDS RAEB II with positive response to chemotherapy, and the increase in proliferative activity of haematopoietic cells of peripheral blood (PB) and bone marrow (BM) was determined in patients with MDS RAEB II in transformation and acute myeloid leukaemia (AML) after MDS.
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Watson, H. Angharad, Rebecca J. Holley, Kia J. Langford-Smith, Fiona L. Wilkinson, Toin H. van Kuppevelt, Robert Wynn, J. Ed Wraith, Catherine L. R. Merry, and Brian W. Bigger. "Excess Heparan Sulphate Inhibits CXCL12-Mediated Hematopoietic Cell Migration and Engraftment After Bone Marrow Transplant in Mice with Mucopolysaccharidosis Type I,." Blood 118, no. 21 (November 18, 2011): 4010. http://dx.doi.org/10.1182/blood.v118.21.4010.4010.
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Abstract Abstract 4010 The primary axis of migration for transplanted hematopoietic stem and progenitor cells (HSPC) is CXCL12/CXCR4. Heparan sulphate (HS) is required for CXCL12 presentation and receptor binding, but the functional role of HS is poorly defined. The alpha-L-iduronidase knockout mouse (Idua−/−) accumulates HS and dermatan sulphate, recapitulating the neurodegenerative lysosomal storage disease Mucopolysaccharidosis I Hurler (MPSIH). MPSIH is primarily treated with HSPC transplant, but clinical experience suggests a historical engraftment defect in patients. We show significantly reduced HSPC migration in Idua−/− recipients and under limiting engraftment conditions we show a significant haematopoietic engraftment defect in Idua−/− recipients. No significant donor cell effect was observed. Bone marrow but not peripheral blood CXCL12 levels are slightly elevated in Idua−/− mice. CFU frequency in BM is unchanged between genotypes but reduced significantly in peripheral blood of Idua−/− mice. In whole bone marrow, and on mesenchymal stem cells from Idua−/− mice, HS is present in significant excess, particularly in extracellular matrix, and cell surface locations, with significant increases in all sulphation modifications, especially 2-O-sulphation. Finally we show that excess HS, and particularly HS with increased 2-O -sulphation, functionally inhibit haematopoietic progenitor cell migration in vitro. These data provide novel insight into the influence of highly sulphated HS in CXCL12 mediated haematopoietic progenitor cell migration and help to explain why HSCT engraftment has been historically low in MPSIH. Disclosures: No relevant conflicts of interest to declare.
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Suljević, Damir, Filip Filipić, and Erna Islamagić. "Emperipolesis: Sternal and Femoral Microenvironment Induces Megakaryiocyte Emperipolesis in the Wistar Strain." Macedonian Veterinary Review 42, no. 1 (March 1, 2019): 71–77. http://dx.doi.org/10.2478/macvetrev-2019-0012.
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AbstractEmperipolesis is considered a physiological phenomena often present in various pathophysiological conditions, but its etiology is still unknown. In this study, we analyzed the number of megakaryocytes and the percentage of emperipoletic cells in the sternal and femoral bone marrow of Wistar rats. Five types in the thrombopoiesis lineage (megakaryoblasts, promegakaryocytes and megakaryocytes - acidophilic, basophilic and thrombocytogenic) were determined. Except for basophilic megakaryocytes, significant differences were found for number of thrombopoietic cells in the sternal and femoral bone marrow. A larger number of thrombocytogenic megakaryocytes were present in the sternal bone marrow. Emperipoletic cells were significantly present in the femoral compared to the sternal bone marrow. Emperipolesis was typical for lymphocytes and neutrophils individually, while emperipolesis with two or more cells within thrombopoietic cell was also present (1-7 %) and significant differences between the sternal and femoral bone marrow were detected. Emperipolesis was found in all analysed rats and it most commonly occured within mature megakaryocytes and rarely megakaryoblasts, while it was not recorded in the promegakaryocytes. The high incidence of megakaryocytes with emperopolesis in rats could be a consequence of “normal” cell retention in the cytoplasm of megakaryocytes while passing blood cells to circulation or related to haematopoietic response due to high incidence of inbreeding.
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Chan, Lap Shu Alan, Rena Buckstein, Marciano D. Reis, Alden Chesney, Adam Lam, Matthew C. Cheung, Eugenia Piliotis, Lilly Chunhong Gu, and Richard A. Wells. "Iron Overload and Haematopoiesis in MDS: Does Blood Transfusion Promote Progression to AML?" Blood 112, no. 11 (November 16, 2008): 2685. http://dx.doi.org/10.1182/blood.v112.11.2685.2685.
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Abstract Introduction: The biology of myelodysplastic syndrome (MDS) is poorly understood, and treatment options are limited. Thus, most MDS patients require chronic red blood cell transfusion, and many develop secondary iron overload. Although the pathophysiological consequences of iron overload to the heart, liver, and endocrine organs have been well characterized, its effects on haematopoiesis have not been studied. However, it has been observed that chelation therapy in iron-overloaded MDS patients may result in reduction of transfusion requirements, and recent studies have suggested a correlation between the use of iron chelation therapy and improvement in leukaemia-free survival in MDS. At the cellular level, iron toxicity is mediated in large part via the generation of reactive oxygen species (ROS). It has been shown in animal models that accumulation of ROS leads to senescence of haematopoietic stem cells, and that ROS cause DNA damage and promote the development of malignancy. These effects of ROS may be particularly important in MDS, in which haematopoiesis is already severely compromised and genetic instability is a striking feature. Hypothesis: We hypothesize that iron overload secondary to transfusion leads to increased levels of intracellular ROS in early haematopoeitic cells in MDS. The increase in intracellular ROS in MDS would be predicted to lead further impairment of haematopoiesis via stem cell exhaustion and while promoting accumulation of DNA damage by myelodysplastic stem cells and early progenitors, thus accelerating progression of MDS to acute leukaemia. Results: To test this hypothesis, we examined the relationship between transfusion-related iron overload and ROS content of CD34+ bone marrow cells in MDS. ROS content was measured in CD34+ cells by flow cytometry in bone marrow aspirates from 34 consecutive MDS patients (CMML=4, MDS/MPD=2, RA=4, RARS=3, RCMD=2, RAEB 1=6, RAEB 2=12, RAEB-t/AML=1). The patients represented a wide range of prior transfusion burden (0->300 units PRBC) and serum ferritin levels (11->10000 μg/L). ROS was strongly correlated with serum ferritin concentration for patients with iron overload (serum ferritin >1000 μg/L; n=14, R=0.733, p<0.005). The correlation between ROS and ferritin level was even stronger in the subset of patients with RAEB 1 or RAEB 2 and iron overload (n=11, R=0.838, p<0.005). In contrast, no correlation between ROS and ferritin level was demonstrated for patients with serum ferritin <1000 μg/L (n=20). Importantly, iron chelation therapy was associated with a reduction in CD34+ cell ROS content in one patient. To assess the effect of iron overload on normal stem cell and progenitor function, we established a mouse model of subacute bone marrow iron overload. B6D2F1 mice were loaded with iron dextran by intraperitoneal injection (150mg total iron load over 21 days), and sacrificed three days after the end of iron loading. Iron staining of tissue sections confirmed iron deposition in the bone marrow, liver, and myocardium. The development of splenomegaly was noted in iron-loaded animals. Flow cytometric analysis revealed increased apoptosis of bone marrow cells in iron loaded mice based on annexin V+/7 AAD-staining (6.26±0.96% versus 3.54±0.99% for control mice, paired student’s t-Test p<0.005). However, ROS content in CD117+ progenitors of iron loaded mice was similar to control mice. Thus, subacute iron loading in mice increases apoptosis but does not alter the ROS content of HSCs; we postulate that chronic iron overload is required to achieve this effect. Conclusions: These results establish a relationship between CD34+ cell ROS content and serum ferritin concentration in MDS patients with iron overload, and indicate that iron chelation therapy in this patient population reverses this ROS accumulation. The physiological consequences of this relationship are currently being investigated in this patient set by haematopoietic colony assays and assessment of DNA damage in CD34+ cells. Nonethelesss, these data may have key implications for the deployment of iron chelation therapy in MDS patients, and may explain the association between the use of iron chelation and improved leukaemia-free survival in MDS.
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Fernandez-Becerra, Carmen, Joel Lelievre, Mireia Ferrer, Nuria Anton, Richard Thomson, Cristina Peligero, Maria Jesus Almela, Marcus VG Lacerda, Esperanza Herreros, and Hernando A. del Portillo. "Red blood cells derived from peripheral blood and bone marrow CD34+ human haematopoietic stem cells are permissive to Plasmodium parasites infection." Memórias do Instituto Oswaldo Cruz 108, no. 6 (September 2013): 801–3. http://dx.doi.org/10.1590/0074-0276108062013019.
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Martin, Catherine Claude, Chantal Jayat-Vignoles, Jean-Luc Faucher, Thaddeus George, Vidya Venkatachalam, Phil Morrissey, and Jean Feuillard. "Novel Multiparametric Quantitative Immunocytomorphological Characterisation of Human Bone Marrow Precursor Differentiation and of Haematopoietic Neoplasms Using ImageStream® Cytometry." Blood 112, no. 11 (November 16, 2008): 4871. http://dx.doi.org/10.1182/blood.v112.11.4871.4871.
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Abstract The ImageStream technology performs high speed acquisition of brightfield, laser scatter and up to four fluorescent images per cell for several thousands of cells in suspension, thereby enabling simultaneous immunophenotyping and morphology-based measurements. This is the only technology combining cytology and flow cytometry in one single platform. Our aim was to study normal and tumour cells of the haematopoietic lineage with this new technology in order to improve diagnosis of haematological disorders. We have defined cytomorphological criteria of normal bone marrow (n=4) and circulating blood cells (n=40). Cells were multi-colour labelled with both DRAQ5 nuclear stain and CD45 ECD-mAb, and additionally labeled with a combination of mAbs against either CD3/CD19, CD11b/CD16, CD14/CRTH2, or CD71/CD235. Results for normal cells were compared to those obtained by classical cytometry and cytology. We then applied these criteria to samples with patients with circulating leukemic cells, including 1 myelodysplatic syndrome (MDS), 1 myeloproliferative syndrome (MPS), 3 acute lymphoblastic leukaemia (ALL), 2 follicular lymphomas (FL) and 20 chronic lymphocytic lymphomas (CLL). We have created completely new quantitative cytomorphological criteria for classifying blood cells using parameters that measure cellular size and shape, nuclear to cytoplasmic area ratio, nuclear lobe count, SSC texture, the ratio between the size and the major axis of CD45, the ratio between the intensity and the compactness of SSC signal, and the intensity of DRAQ5 labelling, to name a few. Using these criteria, we have characterised normal bone marrow differentiation and normal circulating blood cells. We have obtained a perfect correlation with classical cytology and flow cytometry. Analysis of pathological samples showed that abnormal cells were recognized in all cases. We found an abnormal blast cell compartment and an abnormal monocytic differentiation branch in the case of MDS. We have also defined specific cytomorphological properties that distinguish ALL, FL and CLL tumour cells from normal cells. We also provide data that enumerates the proportion of large cells, of atypical CLL cells and of cells in the G2/M phase. Altogether, these results show that a technology combining cytology and flow cytometry in a single platform leads to the discovery of completely new and quantitative cytomorphological parameters defining each stage of normal cell and each category of abnormal cells of the haematopoietic lineage, opening completely new perspectives for the diagnosis of haematopoietic neoplasms.
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Jibril, Aisha, Jayna J. Mistry, Jamie A. Moore, Charlotte Hellmich, Victoria Willimott, Kristian M. Bowles, and Stuart A. Rushworth. "Myeloma Derived Mitochondrial Damage Associated Molecular Patterns Promote Pro-Tumoral Expansion By Inducing a Pro-Inflammatory Signature in the Bone Marrow Microenvironment." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-139811.
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Multiple Myeloma (MM) is a malignancy of antibody producing B cells (plasma cells), leading to the accumulation of tumour cells within the bone marrow (BM) microenvironment. Mitochondrial DNA (mtDNA) is a damage associated molecular pattern (DAMP), the mitochondrial genome contains islands of unmethylated CpG nucleotide motifs that have been shown to activate and promote memory B cell proliferation and antibody secretion. Recent studies have indicated that mtDNA is elevated in the circulation of trauma and cancer patients and have highlighted the need to determine the functional purpose of elevated mtDNA within the BM microenvironment. Here we investigate the hypothesis that multiple myeloma cells secrete mtDNA and other mtDAMPs to induce a pro-inflammatory bone marrow microenvironment, supportive of the progression and survival of MM. As well as investigating how MM affects the haematopoietic stem cell niche through establishing a syngeneic myeloma mouse model. We show that immunocompromised NSG mice transplanted with human MM cell lines released higher levels of MM derived mtDNA detected in the plasma by real-time PCR. Furthermore, in vitro experiments showed that pro-inflammatory cytokines IL-1B, IL-6, and IL-8 were elevated in both primary and cell line myeloma samples upon treatment with CpG oligonucleotides. Murine bone marrow derived macrophages (BMDMs) treated with mtDNA or mtDAMPs showed increased expression of pro-inflammatory cytokines. To understand the significance of the mtDAMP proinflammatory induction, C57BL/6 mice were successfully engrafted with murine 5TGM1 myeloma cell line to establish a syngeneic mouse model. Analysis of the haematopoietic stem and progenitor cell populations showed that 5TGM1 induced the expansion of these cell populations when compared to control WT animals. To understand the significance of mtDAMPs in regulating this HSPC expansion we used blocking antibodies to TLR9 (receptor for mtDNA) and FPR1 (receptor for formylated mitochondrial proteins) in 5TGM1 engrafted animals. Results show that myeloma tumour burden was reduced when FPR1 and TLR9 are blocked compared to control animals. Here we highlight the involvement of mtDAMPs in MM to create a favourable proinflammatory microenvironment which provides the conditions for MM survival and proliferation. This data highlights the importance of mtDAMPs in MM disease progression and suggests targeting these activating receptor pathways may provide a novel therapeutic intervention. Disclosures Bowles: Janssen: Research Funding; AbbVie: Research Funding. Rushworth:Janssen: Research Funding; AbbVie: Research Funding.
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Larghero, J., D. Farge, A. Braccini, S. Lecourt, A. Scherberich, E. Foïs, F. Verrecchia, et al. "Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis." Annals of the Rheumatic Diseases 67, no. 4 (May 25, 2007): 443–49. http://dx.doi.org/10.1136/ard.2007.071233.
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Background:Mesenchymal stem cells (MSCs) have a potential immunomodulatory role in autoimmune disease; however, the qualitative properties and haematopoietic support capacity of MSCs derived from patients with autoimmune disease is unclear.Objectives:To further characterise phenotypically and functionally bone marrow (BM)-derived MSCs from patients with systemic sclerosis (SSc).Methods:Key parameters of BM-derived MSC function and phenotype were assessed in 12 patients with SSc and compared with 13 healthy normal controls. The parameters included the ability to: form colony-forming unit fibroblasts (CFU-F), differentiate along the adipogenic and osteogenic lineages, express cell surface antigens defining the MSCs population, support normal haematopoiesis and suppress in vitro lymphocyte proliferation induced by either anti-CD3∊ plus anti-CD28 monoclonal antibodies or the mixed lymphocyte reaction.Results:SSc MSCs were shown to have a similar characteristic phenotype, capacities to form CFU-F and to differentiate along adipogenic and osteogenic lineages as those of healthy donor MSCs. The ability of SSc MSCs to support long-term haematopoiesis was also identical to that of controls. Both healthy donor and SSc BM MSCs reduced the proliferation of autologous and allogeneic peripheral blood mononuclear cells in a cell number dependent fashion.Conclusions:These results show that BM-derived MSCs from patients with SSc under the described culture conditions exhibit the same phenotypic, proliferative, differentiation potential and immunosuppressive properties as their healthy counterparts and could therefore be considered in an autologous setting. Further studies are needed to ensure the quality and safety of large-scale expansion of patient MSCs prior to their potential use in clinical trials.
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Ichim, Christine V., Dzana Dervovic, Juan Carlo Zuniga-Pflucker, and Richard A. Wells. "The Orphan Nuclear Receptor NR2F6 Is a Novel Negative Regulator of T-Cell Development." Blood 114, no. 22 (November 20, 2009): 915. http://dx.doi.org/10.1182/blood.v114.22.915.915.
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Abstract Abstract 915 The orphan nuclear receptor NR2F6 is a mammalian homologue of the Drosophila seven-up gene that plays key roles in decisions of cell fate in neuroblast and retinal cells. We have previously described a novel role for NR2F6 in decisions of cell fate of mammalian haematopoietic cells of the myeloid cell lineage. We have shown that over-expression of NR2F6 in bone marrow cells impairs differentiation and extends the proliferative capacity of myeloid and early progenitor cells eventually leading to acute myeloid leukaemia (AML), while silencing of NR2F6 expression in AML cell lines causes terminal differentiation and apoptosis. A role of NR2F6 in lymphopoiesis has yet to be identified. Here we describe for the first time a role for NR2F6 in the specification of lymphoid cells. NR2F6 expression is heterogeneous throughout the haematopoietic hierarchy, with expression being highest in long-term repopulating HSCs and generally declining with the differentiation of progenitor cells. We report that over-expression of NR2F6 abrogates the developmental program necessary for T-cell lymphopoiesis. We assessed the effects of NR2F6 on lymphopoiesis in vivo by competitive bone marrow transplantation of NR2F6-IRES-GFP or GFP retrovirally transduced grafts (n=43). Competitive repopulation of lethally irradiated murine hosts with GFP transduced bone marrow cells resulted in successful engraftment and T-cell development, with GFP+ T-cells present in the thymus, and periphery at rates comparable to the percent marked cells in the original graft. However over-expression of NR2F6 placed developing T-cells at a dramatic competitive disadvantage. Six weeks post transplant the proportion of CD3+ cells derived from NR2F6 transduced bone marrow cells was greatly diminished relative to control (more than 10 fold), while at 12 weeks post-transplant we observed an abrogation of CD3+ cells derived from NR2F6 transduced T-cells (with the percentage of NR2F6 transduced CD3+ cells being comparable to staining with IgG control) in both the thymus and periphery. This stark competitive disadvantage was observed in all recipients of NR2F6 transduced grafts. We confirmed that this is not a phenomenon specific to the marker CD3 by analysing a portion of the animals for expression of CD4 and CD8, which again showed a lack of mature t-cells. In a second series of bone marrow transplants, cells transduced with NR2F6 or GFP were purified by fluorescence-activated cell sorting and grafts of 100% transduced cells were transferred by tail vein injection into lethally irradiated recipients. Animals transplanted with NR2F6 transduced bone marrow demonstrated a gross decrease in their thymic size and cellularity (∼10 fold decrease, n=17). Furthermore, the thymus of NR2F6 transduced animals contained a larger proportion of non-transduced, GFP negative residual haematopoietic cells than the vector control animals, corroborating the competitive disadvantage that NR2F6 transduced bone marrow cells face in the thymus. As observed in our previous experiments these animals demonstrated a gross reduction in the proportion of CD3+ cells in the thymus, spleen, lymph nodes and peripheral blood. To rule out the possibility that over-expression of NR2F6 is preventing the trafficking of progenitor cells to the thymus we differentiated NR2F6 or GFP transduced haematopoietic stem cells (lin-,c-kit+,sca-1+) into T-cells in vitro on OP9-DL1 cells. We observed a drastic reduction in the number of cells generated from NR2F6 transduced stem/progenitor cells (>50 fold at day 23), suggesting that expression of NR2F6 greatly impairs T-cell development. Mechanistically, others have shown that NR2F6 functions as a transcriptional repressor inhibiting the transactivating ability of genes such as Runx1. We conjecture that in lymphoid progenitors as well NR2F6 functions as a transcriptional repressor preventing the activation of pathways necessary for T-cell survival, proliferation and lymphopoiesis. Taken together, these data establish that the orphan nuclear receptor NR2F6 is a novel negative regulator of T-cell lymphopoiesis, and demonstrate that down-regulation of NR2F6 is important for the survival and proliferation of T-cell progenitors. Disclosures: No relevant conflicts of interest to declare.
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Wells, Richard A., Kenneth R. Chien, and Pei-Hua Yen. "RXRα Null Haematopoietic Cells Fail To Reconstitute Haematopoiesis in Lethally Irradiated Recipient Mice." Blood 104, no. 11 (November 16, 2004): 2669. http://dx.doi.org/10.1182/blood.v104.11.2669.2669.
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Abstract The retinoid X receptor (RXR) acts as an obligate heterodimeric partner for multiple nuclear hormone receptors (NRs), including the retinoic acid receptor (RAR), thyroid receptor (TR), vitamin D receptor (VDR), and peroxisome proliferator-activated receptor (PPAR). Targeted disruption of RXRα in the mouse yields an embryonic lethal phenotype due to impairment of cardiac development. We have utilized a conditional knockout approach to investigate the roles of NR signaling in haematopoiesis. Bone marrow cells were isolated from a mouse homozygous for a targeted mutation in which exon IV of RXRα is flanked by loxP sites (RXRαfl/fl). This mutation permits normal expression of RXRα, but expression of cre recombinase results in excision of exon IV, abrogating expression of functional RXRα (RXRαko/ko). We employed a retrovirus to deliver cre to conditionally targeted haematopoietic cells. Lineage-depleted RXRαfl/fl bone marrow (BM) cells were transduced with a retrovirus that expresses a GFP-cre fusion, or with a control retrovirus expressing only EGFP. Transduced cells were isolated to >97% purity by FACS. The effect of RXRα disruption on haematopoiesis was assessed by in vitro assays and by transplantation into strain-matched lethally irradiated recipient mice. Progenitor assays performed in methylcellulose medium supplemented with haematopoietic growth factors revealed that GFP-cre - transduced (RXRαko/ko) grafts contain slightly fewer BFU-E and CFU-GM per 10,000 cells (60% and 80% of EGFP - transduced RXRαfl/fl cells, respectively). Long-term culture initiating cells (LTCIC) were enumerated for RXRαko/ko and RXRαfl/fl grafts. RXRα excision resulted in a moderate (25%) reduction in LTCIC. RXRαko/ko HSCs grown in suspension culture (IMDM supplemented with 10% foetal bovine serum, IL3, IL6, and kit ligand) for two weeks show reduced proportions of Mac1 positive (5% vs 27%) and Gr-1 positive (5% vs 12%) cells and strikingly increased CD117 positive cells (84% vs 49%). In vivo function of RXRαko/ko HSCs was evaluated by transplantation into lethally irradiated mice. Recipients were analyzed at 2, 4, and 6 weeks post-transplantation. Two weeks after transplantation, RXRαko/ko and RXRαfl/fl HSCs showed similar patterns of engraftment, with GFP-positive erythroid and myeloid cells found mainly in the spleen. At 4 weeks, recipients of RXRαfl/fl grafts showed significant BM engraftment of myeloid and erythroid lineages, while RXRαko/ko recipients exhibited minimal BM engraftment. At 6 weeks post-transplant, engraftment of RXRαfl/fl cells was well-established in both BM and spleen. RXRαko/ko HSCs showed minimal myeloid engraftment, but both spleen and BM were populated predominantly by Ter119 positive erythroid cells, which exhibit markedly dyserythropoietic morphology. This difference was reflected in peripheral blood counts; recipients of RXRαko/ko grafts were profoundly anaemic, thrombocytopenic, and neutropenic, and pronounced RBC polychromasia and poikilocytosis. These data indicate that disruption of RXRα in adult HSCs results in a modest reduction in early and committed progenitors in vitro, but profoundly disrupts ability to reconstitute haematopoiesis in a lethally irradiated recipient. Myeloid and megakaryocyte lineages do not engraft in recipients of RXRαko/ko HSCs. RXRαko/ko erythropoiesis is dysplastic and yields markedly abnormal erythrocytes. Further investigation is required to elucidate the multiple roles of RXRα in haematopoiesis.
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FORBES, Stuart J., Pamela VIG, Richard POULSOM, Nicholas A. WRIGHT, and Malcolm R. ALISON. "Adult stem cell plasticity: new pathways of tissue regeneration become visible." Clinical Science 103, no. 4 (August 27, 2002): 355–69. http://dx.doi.org/10.1042/cs1030355.
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There has recently been a significant change in the way we think about organ regeneration. In the adult, organ formation and regeneration was thought to occur through the action of organ-or tissue-restricted stem cells (i.e. haematopoietic stem cells making blood; gut stem cells making gut, etc.). However, there is a large body of recent work that has extended this model. Thanks to lineage tracking techniques, we now believe that stem cells from one organ system, for example the haematopoietic compartment, can develop into the differentiated cells within another organ system, such as liver, brain or kidney. This cellular plasticity not only occurs under experimental conditions, but has also been shown to take place in humans following bone marrow and organ transplants. This trafficking is potentially bi-directional, and even differentiated cells from different organ systems can interchange, with pancreatic cells able to form hepatocytes, for example. In this review we will detail some of these findings and attempt to explain their biological significance.
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Budi, Luh Putu Rihayani, Ketut Ariawati, and Sianny Herawati. "NEONATAL ACUTE MYELOID LEUKAEMIA." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 19, no. 3 (October 14, 2016): 211. http://dx.doi.org/10.24293/ijcpml.v19i3.417.
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Acute myeloid leukaemia (AML) is a. malignant, clonally disease that involves proliferation of blasts in bone marrow, blood, or other tissue. The blasts most often show myeloid or monocytic differentiation. The incidence of AML increases with age, but when neonatal leukaemia does occur, it is paradoxically AML rather than ALL. All the signs and symptoms that present on patient with AML are caused by the infiltration of the bone marrow with leukaemic cells and resulting failure of normal haematopoiesis. Without the normal haematopoietic elements, the patient is at risk for developing life-threatening complications of anaemia, infection due to functional neutropenia, and haemorrhage due to thrombocytopenia. Organomegaly is seen in approximately half of patient with AML due to hepatic and sphlanic infiltration with leukaemic blasts. Prognosis of neonatal leukaemia is poor with the 6-month survival rate is only one third despite aggressive chemotherapy. It has higher mortality rate than any other congenital cancer. The researchers reported two of AML diagnosed cases in neonatal period. The first case, a one-day-old male was referred with respiratory distress and suspect Down syndrome with spontaneous petechiae. The second case, a 17-day-old female presented with bloody diarrhoea and history of hypothyroid. Dysmorphic face and hepatosplenomegalia were found in both of the physical examination. Their complete blood count revealed leukocytosis and thrombocytopenia. Peripheral blood smear revealed myeloblast 30% on the first case and 23% on the second case. Both immunophenotyping revealed the population of blast expressing myeloid lineage (CD33 and CD34).
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Juhl, Claus Orloff, Lars Vinter-Jensen, Olaf Myhre-Jensen, Lone Susanne Jensen, and Esam Zapher Dajani. "Systemic Treatment with Epidermal Growth Factor Induces Anaemia in Goettingen Minipigs." Clinical Science 89, no. 4 (October 1, 1995): 453–58. http://dx.doi.org/10.1042/cs0890453.
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1. From two independent experimental studies conducted in 48 minipigs with oesophageal sclerotherapy and concomitant treatment with epidermal growth factor, blood samples together with bone marrow biopsies were analysed for safety data. 2. Four to five weeks of systemic treatment with epidermal growth factor induced a decline in blood haemoglobin concentration in a time- and dose-dependent and reversible manner but without an effect on leucocyte or platelet counts. 3. The bone marrow expressed decreased amounts of haematopoietic tissue and reduced numbers of erythropoietic cells. 4. Four to five weeks of systemic treatment with epidermal growth factor induced reversible increases in serum concentrations of creatinine and urea, most likely reflecting renal impairment. 5. Groups in which creatinine and urea were not increased also had reduced blood haemoglobin concentrations. 6. These findings suggest that epidermal growth factor selectively impaired the erythropoiesis and stress the importance of risk-benefit analysis concerning the potential therapeutic applications of epidermal growth factor.