Journal articles on the topic 'Haematopoiesis'
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1
Štefková, Kateřina, Markéta Hanáčková, Jan Kučera, Katarzyna Anna Radaszkiewicz, Barbora Ambrůžová, Lukáš Kubala, and Jiří Pacherník. "MAPK p38alpha Kinase Influences Haematopoiesis in Embryonic Stem Cells." Stem Cells International 2019 (June 2, 2019): 1–16. http://dx.doi.org/10.1155/2019/5128135.
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The activation of p38alpha kinase mediates cell response to various extracellular factors including many interleukins and growth factors important for haematopoiesis. The role of p38alpha kinase was previously analysed in particular haematopoietic cells. In this study and for the first time, the role of p38alpha kinase in haematopoiesis was studied using a model of continuous haematopoietic development in pluripotent embryonic stem cellsin vitro. The expression of transcripts associated with haematopoiesis and the potential for the formation of specific haematopoietic cell colonies were compared between wild-type and mutant p38alpha gene-depleted cells. The absence of p38alpha kinase led to the inhibition of hemangioblast formation during the first step of haematopoiesis. Later, during differentiation, due to the lack of p38alpha kinase, erythrocyte maturation was impaired. Mutant p38α−/−cells also exhibited decreased potential with respect to the expansion of granulocyte colony-forming units. This effect was reversed in the absence of erythropoietin as shown by colony-forming unit assay in media for colony-forming unit granulocytes/macrophages. p38alpha kinase thus plays an important role in the differentiation of common myeloid precursor cells into granulocyte lineages.
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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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GUILPIN, V. O., L. NOSBISCH, R. G. TITUS, and C. J. SWARDSON-OLVER. "Infection with Leishmania major stimulates haematopoiesis in susceptible BALB/c mice and suppresses haematopoiesis in resistant CBA mice." Parasitology 126, no. 3 (March 2003): 187–94. http://dx.doi.org/10.1017/s0031182002002779.
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Cytokine responses to Leishmania infection begin very early in infection, and differ between susceptible and resistant mice. Susceptibility to chronic Leishmania infection has been associated with increased haematopoiesis. To analyse the effect that acute infection with L. major has on bone-marrow haematopoiesis in susceptible (BALB/c) and resistant (CBA) mice, we enumerated erythroid progenitors and granulocyte-monocyte progenitors 3 days after infection. We found that haematopoiesis was stimulated in BALB/c mice infected with L. major, while haematopoiesis was inhibited in CBA mice. We found that this effect could be partially explained by cytokine production: interleukin-4 was involved in stimulation of BALB/c haematopoiesis and tumour necrosis factor-α was involved in inhibition of CBA haematopoiesis. Our conclusions are that haematopoietic changes occur shortly after L. major infection, and may be related to disease outcome.
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Oliveira, Dalila Cunha, Amanda Nogueira-Pedro, Ed Wilson Santos, Araceli Hastreiter, Graziela Batista Silva, Primavera Borelli, and Ricardo Ambrósio Fock. "A review of select minerals influencing the haematopoietic process." Nutrition Research Reviews 31, no. 2 (July 9, 2018): 267–80. http://dx.doi.org/10.1017/s0954422418000112.
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AbstractMicronutrients are indispensable for adequate metabolism, such as biochemical function and cell production. The production of blood cells is named haematopoiesis and this process is highly consuming due to the rapid turnover of the haematopoietic system and consequent demand for nutrients. It is well established that micronutrients are relevant to blood cell production, although some of the mechanisms of how micronutrients modulate haematopoiesis remain unknown. The aim of the present review is to summarise the effect of Fe, Mn, Ca, Mg, Na, K, Co, iodine, P, Se, Cu, Li and Zn on haematopoiesis. This review deals specifically with the physiological requirements of selected micronutrients to haematopoiesis, showing various studies related to the physiological requirements, deficiency or excess of these minerals on haematopoiesis. The literature selected includes studies in animal models and human subjects. In circumstances where these minerals have not been studied for a given condition, no information was used. All the selected minerals have an important role in haematopoiesis by influencing the quality and quantity of blood cell production. In addition, it is highly recommended that the established nutrition recommendations for these minerals be followed, because cases of excess or deficient mineral intake can affect the haematopoiesis process.
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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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Kondera, Elżbieta. "Haematopoiesis and haematopoietic organs in fish." Roczniki Naukowe Polskiego Towarzystwa Zootechnicznego 15, no. 1 (March 31, 2019): 9–16. http://dx.doi.org/10.5604/01.3001.0013.4535.
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Haematopoiesis is a complex process in which haematopoietic stem cells, the most immature elements of the haematopoietic hierarchy, proliferate and differentiate into various classes of haematopoietic progenitor cells. These progenitor cells have been shown to be able to differentiate into mature blood cells: erythrocytes, lymphocytes, thrombocytes, granulocytes, and monocytes. The pronephros, or head kidney, is a basic organ forming the blood elements, and is also a reservoir of blood cells. Basic haematopoietic structures and mechanisms in fish are similar to those functioning in other vertebrates, and all haematopoietic cell types are very similar to those of mammals.
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Mak, Ka Sin, Alister P. W. Funnell, Richard C. M. Pearson, and Merlin Crossley. "PU.1 and Haematopoietic Cell Fate: Dosage Matters." International Journal of Cell Biology 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/808524.
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The ETS family transcription factor PU.1 is a key regulator of haematopoietic differentiation. Its expression is dynamically controlled throughout haematopoiesis in order to direct appropriate lineage specification. Elucidating the biological role of PU.1 has proved challenging. This paper will discuss how a range of experiments in cell lines and mutant and transgenic mouse models have enhanced our knowledge of the mechanisms by which PU.1 drives lineage-specific differentiation during haematopoiesis.
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Dickson, M. C., J. S. Martin, F. M. Cousins, A. B. Kulkarni, S. Karlsson, and R. J. Akhurst. "Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice." Development 121, no. 6 (June 1, 1995): 1845–54. http://dx.doi.org/10.1242/dev.121.6.1845.
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Transforming growth factor beta 1 (TGF beta 1) is shown here to be required for yolk sac haematopoiesis and endothelial differentiation. Mice with a targeted mutation in the TGF beta 1 gene were examined to determine the cause of prenatal lethality, which occurs in 50% of homozygous TGF beta 1 null (TGF beta 1−/−) conceptions. 50% of TGF beta 1−/− and 25% of TGF beta 1-+-) conceptions. 50% of TGF beta 1−/− and 25% of TGF beta 1+/− conceptuses were found to die at around 10.5 dpc. The primary defects were restricted to extraembryonic tissues, namely the yolk sac vasculature and haematopoietic system. The embryos per se showed developmental retardation, oedema and necrosis, which were probably secondary to the extraembryonic lesions. The defect in vasculogenesis appeared to affect endothelial differentiation, rather than the initial appearance and outgrowth of endothelial cells. Initial differentiation of yolk sac mesoderm to endothelial cells occurred, but defective differentiation resulted in inadequate capillary tube formation, and weak vessels with reduced cellular adhesiveness. Defective haematopoiesis resulted in a reduced erythroid cell number within the yolk sac. Defective yolk sac vasculogenesis and haematopoiesis were present either together, or in isolation of each other. The phenotypes are consistent with the observation of abundant TGF beta 1 gene expression in both endothelial and haematopoietic precursors. The data indicate that the primary effect of loss of TGF beta 1 function in vivo is not increased haematopoietic or endothelial cell proliferation, which might have been expected by deletion of a negative growth regulator, but defective haematopoiesis and endothelial differentiation.
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Keenan, Christine R. "Heterochromatin and Polycomb as regulators of haematopoiesis." Biochemical Society Transactions 49, no. 2 (April 30, 2021): 805–14. http://dx.doi.org/10.1042/bst20200737.
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Haematopoiesis is the process by which multipotent haematopoietic stem cells are transformed into each and every type of terminally differentiated blood cell. Epigenetic silencing is critical for this process by regulating the transcription of cell-cycle genes critical for self-renewal and differentiation, as well as restricting alternative fate genes to allow lineage commitment and appropriate differentiation. There are two distinct forms of transcriptionally repressed chromatin: H3K9me3-marked heterochromatin and H3K27me3/H2AK119ub1-marked Polycomb (often referred to as facultative heterochromatin). This review will discuss the role of these distinct epigenetic silencing mechanisms in regulating normal haematopoiesis, how these contribute to age-related haematopoietic dysfunction, and the rationale for therapeutic targeting of these pathways in the treatment of haematological malignancies.
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De, Ranita, Kulkarni Uday Prakash, and Eunice S. Edison. "Complex Interactions in Regulation of Haematopoiesis—An Unexplored Iron Mine." Genes 12, no. 8 (August 20, 2021): 1270. http://dx.doi.org/10.3390/genes12081270.
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Iron is one of the most abundant metals on earth and is vital for the growth and survival of life forms. It is crucial for the functioning of plants and animals as it is an integral component of the photosynthetic apparatus and innumerable proteins and enzymes. It plays a pivotal role in haematopoiesis and affects the development and differentiation of different haematopoietic lineages, apart from its obvious necessity in erythropoiesis. A large amount of iron stores in humans is diverted towards the latter process, as iron is an indispensable component of haemoglobin. This review summarises the important players of iron metabolism and homeostasis that have been discovered in recent years and highlights the overall significance of iron in haematopoiesis. Its role in maintenance of haematopoietic stem cells, influence on differentiation of varied haematopoietic lineages and consequences of iron deficiency/overloading on development and maturation of different groups of haematopoietic cells have been discussed.
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Karia, Dimple, Robert C. G. Gilbert, Antonio J. Biasutto, Catherine Porcher, and Erika J. Mancini. "The histone H3K4 demethylase JARID1A directly interacts with haematopoietic transcription factor GATA1 in erythroid cells through its second PHD domain." Royal Society Open Science 7, no. 1 (January 2020): 191048. http://dx.doi.org/10.1098/rsos.191048.
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Chromatin remodelling and transcription factors play important roles in lineage commitment and development through control of gene expression. Activation of selected lineage-specific genes and repression of alternative lineage-affiliated genes result in tightly regulated cell differentiation transcriptional programmes. However, the complex functional and physical interplay between transcription factors and chromatin-modifying enzymes remains elusive. Recent evidence has implicated histone demethylases in normal haematopoietic differentiation as well as in malignant haematopoiesis. Here, we report an interaction between H3K4 demethylase JARID1A and the haematopoietic-specific master transcription proteins SCL and GATA1 in red blood cells. Specifically, we observe a direct physical contact between GATA1 and the second PHD domain of JARID1A. This interaction has potential implications for normal and malignant haematopoiesis.
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Bozhilov, Yavor K., Ian Hsu, Elizabeth J. Brown, and Adam C. Wilkinson. "In Vitro Human Haematopoietic Stem Cell Expansion and Differentiation." Cells 12, no. 6 (March 14, 2023): 896. http://dx.doi.org/10.3390/cells12060896.
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The haematopoietic system plays an essential role in our health and survival. It is comprised of a range of mature blood and immune cell types, including oxygen-carrying erythrocytes, platelet-producing megakaryocytes and infection-fighting myeloid and lymphoid cells. Self-renewing multipotent haematopoietic stem cells (HSCs) and a range of intermediate haematopoietic progenitor cell types differentiate into these mature cell types to continuously support haematopoietic system homeostasis throughout life. This process of haematopoiesis is tightly regulated in vivo and primarily takes place in the bone marrow. Over the years, a range of in vitro culture systems have been developed, either to expand haematopoietic stem and progenitor cells or to differentiate them into the various haematopoietic lineages, based on the use of recombinant cytokines, co-culture systems and/or small molecules. These approaches provide important tractable models to study human haematopoiesis in vitro. Additionally, haematopoietic cell culture systems are being developed and clinical tested as a source of cell products for transplantation and transfusion medicine. This review discusses the in vitro culture protocols for human HSC expansion and differentiation, and summarises the key factors involved in these biological processes.
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Vainieri, Maria L., Andrew M. Blagborough, Adam L. MacLean, Myriam L. R. Haltalli, Nicola Ruivo, Helen A. Fletcher, Michael P. H. Stumpf, Robert E. Sinden, and Cristina Lo Celso. "Systematic tracking of altered haematopoiesis during sporozoite-mediated malaria development reveals multiple response points." Open Biology 6, no. 6 (June 2016): 160038. http://dx.doi.org/10.1098/rsob.160038.
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Haematopoiesis is the complex developmental process that maintains the turnover of all blood cell lineages. 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). Infection is known to affect HSCs, with severe and chronic inflammatory stimuli leading to stem cell pool depletion, while acute, non-lethal infections exert transient and even potentiating effects. Both whether this paradigm applies to all infections and whether the HSC response is the dominant driver of the changes observed during stressed haematopoiesis remain open questions. We use a mouse model of malaria, based on natural, sporozoite-driven Plasmodium berghei infection, as an experimental platform to gain a global view of haematopoietic perturbations during infection progression. We observe coordinated responses by the most primitive HSCs and multiple HPCs, some starting before blood parasitaemia is detected. We show that, despite highly variable inter-host responses, primitive HSCs become highly proliferative, but mathematical modelling suggests that this alone is not sufficient to significantly impact the whole haematopoietic cascade. We observe that the dramatic expansion of Sca-1 + progenitors results from combined proliferation of direct HSC progeny and phenotypic changes in downstream populations. We observe that the simultaneous perturbation of HSC/HPC population dynamics is coupled with early signs of anaemia onset. Our data uncover a complex relationship between Plasmodium and its host's haematopoiesis and raise the question whether the variable responses observed may affect the outcome of the infection itself and its long-term consequences on the host.
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Watkins, Nicholas A., Marloes R. Tijssen, Arief Gusnanto, Bernard de Bono, Subhajyoti De, Diego Miranda-Saavedra, Will Angenent, et al. "The HaemAtlas: Characterising Gene Expression in Differentiated Human Blood Cells." Blood 112, no. 11 (November 16, 2008): 2453. http://dx.doi.org/10.1182/blood.v112.11.2453.2453.
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Abstract Haematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell surface receptors. In order to further understand haematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B-cells, cytotoxic and helper T-cells, Natural Killer cells, granulocytes and monocytes using whole genome microarrays. A bioinformatics analysis of this data was performed focusing on transcription factors, immunoglobulin superfamily members and lineage specific transcripts. We observed that the numbers of lineage specific genes varies by two orders of magnitude, ranging from five for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel co-expression patterns for key transcription factors involved in haematopoiesis (eg. GATA3–GFI1 and GATA2–KLF1). This study represents the most comprehensive analysis of gene expression in haematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which is freely accessible, will be invaluable for future studies on haematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.
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Groner, Yoram, Pnina Sachs, and Joseph Lotem. "Leo Sachs. 14 October 1924—12 December 2013." Biographical Memoirs of Fellows of the Royal Society 66 (February 13, 2019): 355–75. http://dx.doi.org/10.1098/rsbm.2018.0027.
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Leo Sachs was a worldwide renowned scientist for his major contributions in several fields. In the mid 1950s he showed that amniocentesis could be used for prenatal diagnosis of sex and blood group antigens. He then focused on various aspects of normal development and cancer, including the control of normal haematopoiesis and leukaemia, carcinogenesis in vitro by polyoma and SV40 tumour viruses, chemical carcinogens and X-rays, chromosomes and the reversibility of cancer, surface membrane changes in malignant cells and suppression of malignancy by inducing differentiation. The cell culture system he established in the early 1960s for the clonal development of normal haematopoietic cells made it possible to analyse the molecular basis of normal haematopoiesis, and discover the proteins that regulate viability, proliferation and differentiation of different blood cell lineages and the changes that drive leukaemia. His studies established significant general concepts, including: the differential responsiveness of cancer cells to normal regulators of development; suppression of myeloid leukaemia by inducing differentiation, bypassing malignancy-driving genetic defects; identification of chromosomes that control tumour suppression; discovering apoptosis as a major mechanism by which WT-p53 suppresses malignancy; and the ability of haematopoietic cytokines to suppress apoptosis in both normal and leukaemic cells. Leo was fortunate to witness his pioneering discoveries and ideas move from the basic science stage to effective clinical applications, using amniocentesis for prenatal detection of genetic abnormalities, augmenting normal haematopoiesis in patients with various haematopoietic deficiencies and suppressing malignancy by inducing differentiation and apoptosis.
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Konieczny, Joanna, and Lorena Arranz. "Updates on Old and Weary Haematopoiesis." International Journal of Molecular Sciences 19, no. 9 (August 29, 2018): 2567. http://dx.doi.org/10.3390/ijms19092567.
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Blood formation, or haematopoiesis, originates from haematopoietic stem cells (HSCs), whose functions and maintenance are regulated in both cell- and cell non-autonomous ways. The surroundings of HSCs in the bone marrow create a specific niche or microenvironment where HSCs nest that allows them to retain their unique characteristics and respond rapidly to external stimuli. Ageing is accompanied by reduced regenerative capacity of the organism affecting all systems, due to the progressive decline of stem cell functions. This includes blood and HSCs, which contributes to age-related haematological disorders, anaemia, and immunosenescence, among others. Furthermore, chronological ageing is characterised by myeloid and platelet HSC skewing, inflammageing, and expanded clonal haematopoiesis, which may be the result of the accumulation of preleukaemic lesions in HSCs. Intriguingly, haematological malignancies such as acute myeloid leukaemia have a high incidence among elderly patients, yet not all individuals with clonal haematopoiesis develop leukaemias. Here, we discuss recent work on these aspects, their potential underlying molecular mechanisms, and the first cues linking age-related changes in the HSC niche to poor HSC maintenance. Future work is needed for a better understanding of haematopoiesis during ageing. This field may open new avenues for HSC rejuvenation and therapeutic strategies in the elderly.
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Stein, Sarah J., Ethan A. Mack, Kelly S. Rome, and Warren S. Pear. "Tribbles in normal and malignant haematopoiesis." Biochemical Society Transactions 43, no. 5 (October 1, 2015): 1112–15. http://dx.doi.org/10.1042/bst20150117.
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The tribbles protein family, an evolutionarily conserved group of pseudokinases, have been shown to regulate multiple cellular events including those involved in normal and malignant haematopoiesis. The three mammalian Tribbles homologues, Trib1, Trib2 and Trib3 are characterized by conserved motifs, including a pseudokinase domain and a C-terminal E3 ligase-binding domain. In this review, we focus on the role of Trib (mammalian Tribbles homologues) proteins in mammalian haematopoiesis and leukaemia. The Trib proteins show divergent expression in haematopoietic cells, probably indicating cell-specific functions. The roles of the Trib proteins in oncogenesis are also varied and appear to be tissue-specific. Finally, we discuss the potential mechanisms by which the Trib proteins preferentially regulate these processes in multiple cell types.
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González-López, Oscar, Javier I. Muñoz-González, Alberto Orfao, Iván Álvarez-Twose, and Andrés C. García-Montero. "Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis." Cancers 14, no. 10 (May 18, 2022): 2487. http://dx.doi.org/10.3390/cancers14102487.
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Systemic mastocytosis (SM) is a rare clonal haematopoietic stem cell disease in which activating KIT mutations (most commonly KIT D816V) are present in virtually every (>90%) adult patient at similar frequencies among non-advanced and advanced forms of SM. The KIT D816V mutation is considered the most common pathogenic driver of SM. Acquisition of this mutation early during haematopoiesis may cause multilineage involvement of haematopoiesis by KIT D816V, which has been associated with higher tumour burden and additional mutations in other genes, leading to an increased rate of transformation to advanced SM. Thus, among other mutations, alterations in around 30 genes that are also frequently mutated in other myeloid neoplasms have been reported in SM cases. From these genes, 12 (i.e., ASXL1, CBL, DNMT3A, EZH2, JAK2, KRAS, NRAS, SF3B1, RUNX1, SF3B1, SRSF2, TET2) have been recurrently reported to be mutated in SM. Because of all the above, assessment of multilineage involvement of haematopoiesis by the KIT D816V mutation, in the setting of multi-mutated haematopoiesis as revealed by a limited panel of genes (i.e., ASXL1, CBL, DNMT3A, EZH2, NRAS, RUNX1 and SRSF2) and associated with a poorer patient outcome, has become of great help to identify SM patients at higher risk of disease progression and/or poor survival who could benefit from closer follow-up and eventually also early cytoreductive treatment.
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Thorpe, Robin, and Meenu Wadhwa. "Haematopoietic growth factors and their therapeutic use." Thrombosis and Haemostasis 99, no. 11 (2008): 863–73. http://dx.doi.org/10.1160/th07-11-0703.
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SummaryHaematopoietic growth factors constitute an important group of proteins that predominantly regulate the process of haematopoiesis. While some of these proteins have a very broad array of action on very early haematopoietic progenitors leading to multi-lineage increases in haematopoietic cell production and differentiation, others act in a restricted manner on specific committed terminally differentiated cell types. On the basis of their unique spectrum of activities, several factors are approved for clinical use in various indications while others are under investigation in the clinic either alone or as combination therapy. In this review, we have described factors which directly and in some cases indirectly influence haematopoiesis with particular focus on those factors which are either approved or show potential for clinical use. A brief description of the products that are currently available for clinical use is also provided. At present, several new products which include fusion proteins, peptide mimetics are either at the pre-clinical stage or in clinical development for various indications and these are also briefly described.
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Huntly, Brian. "Abstract IA006: Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): IA006. http://dx.doi.org/10.1158/1538-7445.cancepi22-ia006.
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Abstract Interactions between transcription factors (TF) and chromatin factors (CF) regulate gene expression programmes to determine cellular fate. However, unlike for TF, the exact role of CF in this process is poorly understood. Using haematopoiesis as a model system, we address this fundamental question in lineage choice of normal haematopoiesis and the maintenance of acute myeloid leukaemia (AML). To do this, we have functionally characterized the requirement ex vivo of 550 CFs in normal lineage differentiation and further dissected, with single-cell resolution, the roles of 40 CFs during in vivo lineage commitment (using Perturb-seq). Further, utilizing epigenetic profiling (ATAC-seq and ChIP-seq) we have probed TF-CF interactions that have lineage regulatory potential. Finally, we compare the functions of key CFs and their TF-associations between normal and malignant haematopoiesis. These studies demonstrate, both ex vivo and in vivo, that similar complexes, including three MLL-H3K4 COMPASS methyltransferases (KMTs) and non-canonical (nc-BAF) and canonical BAF (c-BAF) complexes, regulate disparate lineage decisions across haematopoiesis. However, somewhat paradoxically, we demonstrate that unrelated Repressive complexes function similarly, but non-redundantly, to restrain excessive myeloid differentiation and protect lineage diversity. We identify interactions between CF and TF that explain the regulatory function of CF and demonstrate that KO of the nc-BAF member Brd9 leads to a premalignant accumulation of myeloid progenitors, related to impaired recruitment of late myeloid TFs. Finally, utilizing similar experiments in a relevant murine AML model, we identify perturbations of MLL-, BAF- and Repressive CF that trigger partial differentiation and loss of leukaemia potential. Our data also highlight opposing functions for the same CF in normal and malignant haematopoiesis. CFs such as COMPASS members and cBAF remodelers are critical for the balanced differentiation of specific normal haematopoietic lineages, however the same CF are critical for the maintenance of leukaemia fitness, where they act predominantly to maintain differentiation blockade. Finally, we demonstrate that this altered effect occurs through the differential utilization of TF by CF complexes between normal and malignant haematopoiesis, such as corrupted Stat5a-CF interactions, potentially identifying specific CF-TF complexes as therapeutic targets in AML. Taken all together, our work greatly elucidates the role of CF and their TF partners across normal and malignant haematopoiesis. Citation Format: Brian Huntly. Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA006.
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Kawa, Miłosz Piotr, Katarzyna Grymuła, Edyta Paczkowska, Magdalena Baśkiewicz-Masiuk, Elżbieta Dąbkowska, Monika Koziołek, Maciej Tarnowski, et al. "Clinical relevance of thyroid dysfunction in human haematopoiesis: biochemical and molecular studies." European Journal of Endocrinology 162, no. 2 (February 2010): 295–305. http://dx.doi.org/10.1530/eje-09-0875.
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ObjectiveAbnormalities in haematological parameters have been noted in patients with thyroid diseases. Nevertheless, the exact mechanism of thyroid hormones' (THs) action on human haematopoiesis is still not entirely clear.DesignThe influence of THs through TH receptors (TRα-1 and TRβ-1) on haematopoiesis in patients with hypo- and hyperthyroidism was analysed.MethodsTR gene expression at the mRNA and protein levels in human CD34+-enriched haematopoietic progenitor cells (HPCs) obtained from the peripheral blood of patients with thyroid disorders and healthy volunteers was analysed. The cell populations were also investigated for clonogenic growth of granulocyte macrophage-colony forming units and erythrocyte-burst forming units (BFU-E). The level of apoptosis was determined by annexin V/propidium iodide staining and quantitative RT-PCR.ResultsThe studies revealed that hypo- and hyperthyroidism modify TR gene expression in HPCs in vivo. TH deficiency resulted in a decrease in total blood counts and clonogenic potential of BFU-E. In contrast, hyperthyroid patients presented increased clonogenic growth and BFU-E number and significantly higher expressions of cell cycle-regulating genes such as those for PCNA and cyclin D1. Finally, an increase in the frequency of apoptotic CD34+-enriched HPCs in hypo- and hyperthyroidism with a modulation of apoptosis-related genes was detected.ConclusionsThe following conclusions were derived: i) TR expression in human haematopoietic cells depends on TH status, ii) both hypo- and hyperthyroidism significantly influence clonogenicity and induce apoptosis in CD34+-enriched HPCs and iii) the molecular mechanism by which THs influence haematopoiesis might provide a basis for designing novel therapeutic interventions in thyroid diseases.
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Dragoljevic, Dragana, Marit Westerterp, Camilla Bertuzzo Veiga, Prabhakara Nagareddy, and Andrew J. Murphy. "Disordered haematopoiesis and cardiovascular disease: a focus on myelopoiesis." Clinical Science 132, no. 17 (September 5, 2018): 1889–99. http://dx.doi.org/10.1042/cs20180111.
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Cardiovascular (CV) diseases (CVD) are primarily caused by atherosclerotic vascular disease. Atherogenesis is mainly driven by recruitment of leucocytes to the arterial wall, where macrophages contribute to both lipid retention as well as the inflammatory milieu within the vessel wall. Consequently, diseases which present with an enhanced abundance of circulating leucocytes, particularly monocytes, have also been documented to accelerate CVD. A host of metabolic and inflammatory diseases, such as obesity, diabetes, hypercholesteraemia, and rheumatoid arthritis (RA), have been shown to alter myelopoiesis to exacerbate atherosclerosis. Genetic evidence has emerged in humans with the discovery of clonal haematopoiesis of indeterminate potential (CHIP), resulting in a disordered haematopoietic system linked to accelerated atherogenesis. CHIP, caused by somatic mutations in haematopoietic stem and progenitor cells (HSPCs), consequently provide a proliferative advantage over native HSPCs and, in the case of Tet2 loss of function mutation, gives rise to inflammatory plaque macrophages (i.e. enhanced interleukin (IL)-1β production). Together with the recent findings of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial that revealed blocking IL-1β using Canakinumab reduced CV events, these studies collectively have highlighted a pivotal role of IL-1β signalling in a population of people with atherosclerotic CVD. This review will explore how haematopoiesis is altered by risk-factors and inflammatory disorders that promote CVD. Further, we will discuss some of the recent genetic evidence of disordered haematopoiesis in relation to CVD though the association with CHIP and suggest that future studies should explore what initiates HSPC mutations, as well as how current anti-inflammatory agents affect CHIP-driven atherosclerosis.
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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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Carmichael, Catherine L., and Jody J. Haigh. "The Snail Family in Normal and Malignant Haematopoiesis." Cells Tissues Organs 203, no. 2 (2017): 82–98. http://dx.doi.org/10.1159/000448655.
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Snail family proteins are key inducers of the epithelial-mesenchymal transition (EMT), a critical process required for normal embryonic development. They have also been strongly implicated in regulating the EMT-like processes required for tumour cell invasion, migration, and metastasis. Whether these proteins also contribute to normal blood cell development, however, remains to be clearly defined. Increasing evidence supports a role for the Snail family in regulating cell survival, migration, and differentiation within the haematopoietic system, as well as potentially an oncogenic role in the malignant transformation of haematopoietic stem cells. This review will provide a broad overview of the Snail family, including key aspects of their involvement in the regulation and development of solid organ cancer, as well as a discussion on our current understanding of Snail family function during normal and malignant haematopoiesis.
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Ranzoni, Anna M., Paulina M. Strzelecka, and Ana Cvejic. "Application of single-cell RNA sequencing methodologies in understanding haematopoiesis and immunology." Essays in Biochemistry 63, no. 2 (June 11, 2019): 217–25. http://dx.doi.org/10.1042/ebc20180072.
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Abstract The blood and immune system are characterised by utmost diversity in its cellular components. This heterogeneity can solely be resolved with the application of single-cell technologies that enable precise examination of cell-to-cell variation. Single-cell transcriptomics is continuously pushing forward our understanding of processes driving haematopoiesis and immune responses in physiological settings as well as in disease. Remarkably, in the last five years, a number of studies involving single-cell RNA sequencing (scRNA-seq) allowed the discovery of new immune cell types and revealed that haematopoiesis is a continuous rather than a stepwise process, thus challenging the classical haematopoietic lineage tree model. This review summarises the most recent studies which applied scRNA-seq to answer outstanding questions in the fields of haematology and immunology and discusses the present challenges and future directions.
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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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Capo-Chichi, Jose-Mario, Phillip Michaels, Rosemarie Tremblay-Le May, Sagi Abelson, Robert Paul Hasserjian, and Daniel Xia. "Emerging patterns in clonal haematopoiesis." Journal of Clinical Pathology 72, no. 7 (June 4, 2019): 453–59. http://dx.doi.org/10.1136/jclinpath-2019-205851.
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Clonal haematopoiesis (CH) is defined by the presence of acquired mutations and/or cytogenetic abnormalities in haematopoietic cells. By definition, these premalignant clones do not meet criteria for haematopoietic neoplasms listed in the Revised Fourth Edition of the WHO classification. CH is fairly common in elderly individuals and is associated with higher risks for haematological cancers, in particular myelodysplastic syndrome and acute myeloid leukaemia (AML), as well as cardiovascular events. Similar small clones have also been detected during follow-up in patients with AML in morphological remission, in individuals with aplastic anaemia, and in pre-chemotherapy blood samples from patients with other types of cancers. In each of these contexts, the presence of mutations carries different clinical implications, and sometimes demonstrates unique genetic profiles. Emerging research suggests that the number and identity of mutations, the size of the mutant clones and various other factors, including age, immune status and history of exogenous drugs/toxins, are important for disease biology and progression. This review focuses specifically on the subset of CH with gene mutations detected by sequencing, and includes discussions of nomenclature and molecular technologies that detect and quantify gene mutations.
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Choi, Philip Y‐I. "Perinephric haematopoiesis." Medical Journal of Australia 188, no. 4 (February 2008): 250. http://dx.doi.org/10.5694/j.1326-5377.2008.tb01598.x.
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Crozatier, Michèle, and Marie Meister. "Drosophila haematopoiesis." Cellular Microbiology 9, no. 5 (May 2007): 1117–26. http://dx.doi.org/10.1111/j.1462-5822.2007.00930.x.
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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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Baccini, Federica, Monica Bianchini, and Filippo Geraci. "Graph-Based Integration of Histone Modification Profiles." Mathematics 10, no. 11 (May 27, 2022): 1842. http://dx.doi.org/10.3390/math10111842.
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In this work, we introduce a similarity-network-based approach to explore the role of interacting single-cell histone modification signals in haematopoiesis—the process of differentiation of blood cells. Histones are proteins that provide structural support to chromosomes. They are subject to chemical modifications—acetylation or methylation—that affect the degree of accessibility of genes and, in turn, the formation of different phenotypes. The concentration of histone modifications can be modelled as a continuous signal, which can be used to build single-cell profiles. In the present work, the profiles of cell types involved in haematopoiesis are built based on all the major histone modifications (i.e., H3K27ac, H3K27me3, H3K36me3, H3K4me1, H3K4me3, H3K9me3) by counting the number of peaks in the modification signals; then, the profiles are used to compute modification-specific similarity networks among the considered phenotypes. As histone modifications come as interacting signals, we applied a similarity network fusion technique to integrate these networks in a unique graph, with the aim of studying the simultaneous effect of all the modifications for the determination of different phenotypes. The networks permit defining of a graph-cut-based separation score for evaluating the homogeneity of subgroups of cell types corresponding to the myeloid and lymphoid phenotypes in the classical representation of the haematopoietic tree. Resulting scores show that separation into myeloid and lymphoid phenotypes reflects the actual process of haematopoiesis.
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Ansell, J. D., K. Samuel, D. G. Whittingham, C. E. Patek, K. Hardy, A. H. Handyside, K. W. Jones, A. L. Muggleton-Harris, A. H. Taylor, and M. L. Hooper. "Hypoxanthine phosphoribosyl transferase deficiency, haematopoiesis and fertility in the mouse." Development 112, no. 2 (June 1, 1991): 489–98. http://dx.doi.org/10.1242/dev.112.2.489.
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We have looked for effects of deficiency in hypoxanthine phosphoribosyl transferase (HPRT) in the mouse comparable to non-behavioural consequences of HPRT-deficiency in humans. HPRT-deficient humans show abnormalities in haematopoiesis and, in heterozygotes, there is strong selection in haematopoietic tissues against HPRT-deficient cells arising as a result of X-chromosome inactivation. We have examined two situations in mice in which HPRT- and HPRT+ cells occur in the same individual. First, in chimaeras resulting from the injection of HPRT- embryonal stem cells into HPRT+ blastocysts the fate of HPRT- and HPRT+ cell populations was monitored by their expression of different isozymes of glucose phosphate isomerase and also, in those chimaeras that resulted from injecting the male ES cells into female blastocysts, by in situ hybridisation using a Y-chromosome-specific repetitive DNA probe. There was a small statistically significant selection against the HPRT- population in haematopoietic tissues in both XX in equilibrium with XY and XY in equilibrium with XY chimaeras. Second, in female mice doubly heterozygous for HPRT-deficiency and for an electrophoretic variant of the X-linked enzyme phosphoglycerate kinase, there was a similar small statistically significant selection against the HPRT- population in haematopoietic tissues. While further work is required to establish whether this selection is a consequence of the HPRT mutation, it is clear that any selection against cells in the haematopoietic system as a consequence of HPRT-deficiency is at most small compared with the effect seen in humans. In HPRT-deficient human males surviving beyond the normal age of puberty, there is testicular atrophy. However, we find no effect of HPRT-deficiency on the fertility of either male or female mice. Thus, as with effects on behaviour, the consequences of HPRT-deficiency for haematopoiesis and testis development in the mouse are at most small compared with those in the human. We conclude that the reason for the difference in effects between the two species lies in a difference in purine-related intermediary metabolism per se, rather than in its interaction with brain amine biochemistry.
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Bruveris, Freya F., Elizabeth S. Ng, Ana Rita Leitoguinho, Ali Motazedian, Katerina Vlahos, Koula Sourris, Robyn Mayberry, et al. "Human yolk sac-like haematopoiesis generates RUNX1-, GFI1- and/or GFI1B-dependent blood and SOX17-positive endothelium." Development 147, no. 20 (October 7, 2020): dev193037. http://dx.doi.org/10.1242/dev.193037.
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ABSTRACTThe genetic regulatory network controlling early fate choices during human blood cell development are not well understood. We used human pluripotent stem cell reporter lines to track the development of endothelial and haematopoietic populations in an in vitro model of human yolk-sac development. We identified SOX17−CD34+CD43− endothelial cells at day 2 of blast colony development, as a haemangioblast-like branch point from which SOX17−CD34+CD43+ blood cells and SOX17+CD34+CD43− endothelium subsequently arose. Most human blood cell development was dependent on RUNX1. Deletion of RUNX1 only permitted a single wave of yolk sac-like primitive erythropoiesis, but no yolk sac myelopoiesis or aorta-gonad-mesonephros (AGM)-like haematopoiesis. Blocking GFI1 and/or GFI1B activity with a small molecule inhibitor abrogated all blood cell development, even in cell lines with an intact RUNX1 gene. Together, our data define the hierarchical requirements for RUNX1, GFI1 and/or GFI1B during early human haematopoiesis arising from a yolk sac-like SOX17-negative haemogenic endothelial intermediate.
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Zaidan, Nada, and Katrin Ottersbach. "The multi-faceted role of Gata3 in developmental haematopoiesis." Open Biology 8, no. 11 (November 2018): 180152. http://dx.doi.org/10.1098/rsob.180152.
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The transcription factor Gata3 is crucial for the development of several tissues and cell lineages both during development as well as postnatally. This importance is apparent from the early embryonic lethality following germline Gata3 deletion, with embryos displaying a number of phenotypes, and from the fact that Gata3 has been implicated in several cancer types. It often acts at the level of stem and progenitor cells in which it controls the expression of key lineage-determining factors as well as cell cycle genes, thus being one of the main drivers of cell fate choice and tissue morphogenesis. Gata3 is involved at various stages of haematopoiesis both in the adult as well as during development. This review summarizes the various contributions of Gata3 to haematopoiesis with a particular focus on the emergence of the first haematopoietic stem cells in the embryo—a process that appears to be influenced by Gata3 at various levels, thus highlighting the complex nature of Gata3 action.
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Ceccacci, Elena, Emanuela Villa, Fabio Santoro, Saverio Minucci, Christiana Ruhrberg, and Alessandro Fantin. "A Refined Single Cell Landscape of Haematopoiesis in the Mouse Foetal Liver." Journal of Developmental Biology 11, no. 2 (March 23, 2023): 15. http://dx.doi.org/10.3390/jdb11020015.
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During prenatal life, the foetal liver is colonised by several waves of haematopoietic progenitors to act as the main haematopoietic organ. Single cell (sc) RNA-seq has been used to identify foetal liver cell types via their transcriptomic signature and to compare gene expression patterns as haematopoietic development proceeds. To obtain a refined single cell landscape of haematopoiesis in the foetal liver, we have generated a scRNA-seq dataset from a whole mouse E12.5 liver that includes a larger number of cells than prior datasets at this stage and was obtained without cell type preselection to include all liver cell populations. We combined mining of this dataset with that of previously published datasets at other developmental stages to follow transcriptional dynamics as well as the cell cycle state of developing haematopoietic lineages. Our findings corroborate several prior reports on the timing of liver colonisation by haematopoietic progenitors and the emergence of differentiated lineages and provide further molecular characterisation of each cell population. Extending these findings, we demonstrate the existence of a foetal intermediate haemoglobin profile in the mouse, similar to that previously identified in humans, and a previously unidentified population of primitive erythroid cells in the foetal liver.
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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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Mitchell, Emily, Michael Spencer Chapman, Nicholas Williams, Kevin J. Dawson, Nicole Mende, Emily Calderbank, Hyunchul Jung, et al. "Clonal Dynamics of Normal Haematopoiesis with Human Ageing." Blood 138, Supplement 1 (November 5, 2021): 598. http://dx.doi.org/10.1182/blood-2021-150152.
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Abstract The haematopoietic system manifests several age-associated phenotypes including anaemia; loss of regenerative capacity, especially in the face of insults such as infection, chemotherapy or blood loss; and increased risk of clonal haematopoiesis and blood cancers. The cellular alterations that underpin these age-related phenotypes, which typically manifest in individuals aged over 70, remain elusive. We aimed to investigate whether changes in HSC population structure with age might underlie any aspects of haematopoietic system ageing. We sequenced 3579 genomes from single-cell-derived colonies of haematopoietic stem cell/multipotent progenitors (HSC/MPPs) from 10 haematologically normal subjects aged 0-81 years. HSC/MPPs accumulated 17 somatic mutations/year after birth with no increased rate of mutation accumulation in the elderly. HSC/MPP telomere length declined by 30 bp/yr. In cord blood and adults aged <65, a small proportion of HSC/MPPs had unexpectedly long telomeres, as assessed using several criteria for outliers. The proportion of cells with unexpectedly long telomeres reduced in frequency with age. Given that telomeres shorten at cell division, these outlier cells have presumably undergone fewer historic cell divisions, supporting the existence of a rare population of dormant HSCs in humans that declines in frequency with age. To interrogate changes in HSC population structure with age, we used the pattern of unique and shared mutations between the sampled cells from each individual to reconstruct their phylogenetic relationships. The frequency of branch-points (known as coalescences) in phylogenetic trees in a neutrally evolving, well-mixed population of somatic cells is primarily determined by the product of population size and time between symmetric self-renewal cell divisions (Nt). Smaller populations and more frequent symmetric divisions both increase the density of coalescences. Specific clones can come to dominate either through neutral drift or positive selection. We found that haematopoiesis in adults aged <65 was polyclonal, with high indices of clonal diversity. The number and pattern of coalescent events in the phylogenies showed that a stable population of 20,000 to 200,000 HSC/MPPs was contributing evenly to blood production in young adult life. In contrast, haematopoiesis in individuals aged >75 showed profoundly decreased clonal diversity. In each elderly subject, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before age 40, but only 22% had known driver mutations. We used the ratio of non-synonymous to synonymous mutations (dN/dS) to identify any excess of non-synonymous (driver) mutations in the dataset. This genome-wide selection analysis estimated that 1/34 to 1/12 non-synonymous mutations were drivers, occurring at a constant rate throughout life, such that the set of 300 - 400 HSC/MPPs sampled from each adult individual harboured around 100 driver mutations, over 10-fold higher than the number of known drivers we could identify. Novel drivers affected a wider pool of genes than identified in blood cancers. The genes DNMT3A, ZNF318 and HIST2H3D were identified as being under significant positive selection in HSC/MPPs, despite ZNF318 and HIST2H3D not being enriched in the setting of myeloid malignancies. Loss of Y chromosome conferred selective benefits on HSC/MPPs in males. Simulations from a simple model of haematopoiesis, with constant HSC population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure observed in the elderly, which could not be explained by neutral models incorporating drift alone. Our data supports the view that dramatically decreased clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently known. By old age the majority of HSCs harbour at least one driver mutation. With such ubiquity of driver mutations, selected purely for their competitive advantage within the stem cell compartment, and with the wholesale rewiring of cellular pathways they induce, it is feasible that they may contribute to age-related phenotypes beyond the increased risk of blood cancer. Disclosures Spencer: Wugen, Inc.: Consultancy, Other: Stock Options. Vassiliou: Kymab Ltd: Divested equity in a private or publicly-traded company in the past 24 months; STRM.BIO: Consultancy; Astrazeneca: Consultancy. Kent: STRM.bio: Research Funding. Campbell: Mu Genomics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees.
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HARMS, Gesche, Regine KRAFT, Gerlinde GRELLE, Bärbel VOLZ, Jens DERNEDDE, and Rudolf TAUBER. "Identification of nucleolin as a new L-selectin ligand." Biochemical Journal 360, no. 3 (December 10, 2001): 531–38. http://dx.doi.org/10.1042/bj3600531.
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Apart from leucocyte–endothelial interactions, the adhesion molecule L-selectin mediates the homotypic adhesion of leucocytes during recruitment at sites of acute inflammation, as well as intercellular adhesion of haematopoietic progenitor cells during haematopoiesis. There is evidence that, in addition to P-selectin glycoprotein ligand-1, other as-yet-unidentified proteins function as L-selectin ligands on human leucocytes and haematopoietic progenitor cells. In the present study, we show: (i) by affinity chromatography on L-selectin–agarose; (ii) by protein identification using MS; and (iii) by covalent cell-surface labelling with sulphosuccinimidyl-2-(biotinamido)ethyl-1,3-dithiopropionate that the multifunctional nuclear protein nucleolin is partly exposed on the cell surface, and is a ligand of L-selectin in human leucocytes and haematopoietic progenitor cells.
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Denizot, Y., and V. Praloran. "PAF and Haematopoiesis. I. 5-Fluoro-Uracil Induces PAF Production in Haematopoietic Organs of Rats." Mediators of Inflammation 3, no. 1 (1994): 23–25. http://dx.doi.org/10.1155/s0962935194000049.
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Haematopoietic organs of rats were examined for the presence of platelet-activating factor (PAF) and acetylhydrolase before and after treatment with 5-fluoro-uracil (5-FU) (200 mg/kg) a chemotherapeutic compound with apoptotic effects. PAF was reported in thymus, spleen and femoral bone marrow of rats with or without 5-FU. Although acetylhydrolase activity in organs was not affected by 5-FU treatment, elevated levels of PAF were observed in thymus and spleen. For the first time PAF is reported in haematopoietic organs of rats, strengtheningin vitrodata suggesting its role in the apoptotic processes in thymus, in the modulation of the immune response, and in the regulation of haematopoiesis.
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Fadini, Gian Paolo, Anurag Mehta, Devinder Singh Dhindsa, Benedetta Maria Bonora, Gopalkrishna Sreejit, Prabhakara Nagareddy, and Arshed Ali Quyyumi. "Circulating stem cells and cardiovascular outcomes: from basic science to the clinic." European Heart Journal 41, no. 44 (December 31, 2019): 4271–82. http://dx.doi.org/10.1093/eurheartj/ehz923.
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Abstract The cardiovascular and haematopoietic systems have fundamental inter-relationships during development, as well as in health and disease of the adult organism. Although haematopoietic stem cells (HSCs) emerge from a specialized haemogenic endothelium in the embryo, persistence of haemangioblasts in adulthood is debated. Rather, the vast majority of circulating stem cells (CSCs) is composed of bone marrow-derived HSCs and the downstream haematopoietic stem/progenitors (HSPCs). A fraction of these cells, known as endothelial progenitor cells (EPCs), has endothelial specification and vascular tropism. In general, the levels of HSCs, HSPCs, and EPCs are considered indicative of the endogenous regenerative capacity of the organism as a whole and, particularly, of the cardiovascular system. In the last two decades, the research on CSCs has focused on their physiologic role in tissue/organ homoeostasis, their potential application in cell therapies, and their use as clinical biomarkers. In this review, we provide background information on the biology of CSCs and discuss in detail the clinical implications of changing CSC levels in patients with cardiovascular risk factors or established cardiovascular disease. Of particular interest is the mounting evidence available in the literature on the close relationships between reduced levels of CSCs and adverse cardiovascular outcomes in different cohorts of patients. We also discuss potential mechanisms that explain this association. Beyond CSCs’ ability to participate in cardiovascular repair, levels of CSCs need to be interpreted in the context of the broader connections between haematopoiesis and cardiovascular function, including the role of clonal haematopoiesis and inflammatory myelopoiesis.
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Kitano, Hisataka, Souichi Aizawa, Emily Chang, Kanako Yamagata, Hiromasa Takayama, and Tempei Kawano. "Tongue cancer developing after haematopoietic stem cell transplantation for treatment of acute promyelocytic leukaemia: a case report." Journal of the Pakistan Medical Association 74, no. 5 (April 22, 2024): 984–86. http://dx.doi.org/10.47391/jpma.9770.
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Acute promyelocytic leukaemia (APL) is a form of acute myelogenous leukaemia. APL is characterised by anaemia due to suppression of normal haematopoiesis and infection. Haematopoietic stem cell transplantation (HSCT) is current option for the treatment of haematopoietic malignancies and is proving to be successful. Although HSCT has been effective for the treatment of haematopoietic malignant tumours, chronic graft-versus-host disease (GVHD) but secondary cancers can occur, which is a serious complication and frequently involves the oral cavity and skin. Here, we report the case of tongue cancer occurring 17 years after transplantation in a patient who developed GVHD after haematopoietic stem cell transplantation and APL remission. To the best of our knowledge, this is the first report of secondary oral cancer after HSCT with APL as the primary disease. Keywords: Chronic graft versus host disease, Haematopoietic stem cell transplantation, Oral squamous cell carcinoma, Secondary cancer.
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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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Göttgens, Berthold, Ian J. Donaldson, Michael Chapman, Sarah Kinston, Josette Renée Landry, Kathy Knezevic, Sandie Piltz, Noel Buckley, and Anthony Green. "Genome-Wide Identification of Cis-Regulatory Sequences Controlling Blood and Endothelial Development." Blood 104, no. 11 (November 16, 2004): 1616. http://dx.doi.org/10.1182/blood.v104.11.1616.1616.
Full textAbstract:
Abstract Haematopoiesis has long served as a paradigm for adult stem cell systems and studies over the last 20 years have established that transcriptional control is central to the specification and subsequent differentiation of haematopoietic stem cells (HSCs). With many of the key transcription factors known, haematopoiesis provides a powerful cellular system for the analysis of mammalian gene regulatory networks. The key missing ingredient, particularly for the stem and progenitor cell stages, is a set of experimentally validated gene regulatory regions together with a molecular understanding of their biological activity. Despite progress in lower organisms, genome-wide computational identification of mammalian cis-regulatory sequences has been hindered by increased genomic complexity and cumbersome transgenic assays. In order to identify transcriptional control regions active during early embryonic haematopoietic development, we have developed a strategy that is based upon a haematopoietic stem cell enhancer (+19 enhancer) identified downstream of the SCL transcription factor, a key regulator of haematopoietic stem cell formation. Starting with this well-characterised blood stem cell enhancer, we have developed computational tools which allow genome-wide identification of functionally related enhancers. This approach has been used to identify novel enhancers involved in the regulation of early blood and endothelial development, and which exhibit predicted biological activity in vitro and in transgenic mice. Transcription factors binding to these enhancers have been identified by chromatin immunoprecipitation. Our data allow the construction of an experimentally verified nascent transcriptional network, which controls the development of blood and endothelium, and which so far contains the SCL, GATA-2, Fli-1, Elf-1 and Hex transcription factors. Additional candidate members of the network have been identified and are being subjected to functional validation. This approach represents a widely applicable strategy for characterising the transcriptional networks controlling a broad range of mammalian developmental programmes.
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Durandt, C., JC Potgieter, J. Mellet, Candice Herd, R. Khoosal, J. G. Nel, T. Rossouw, and M. S. Pepper. "HIV and haematopoiesis." South African Medical Journal 109, no. 8b (September 10, 2019): 40. http://dx.doi.org/10.7196/samj.2019.v109i8b.13829.
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Ozdogu, Hakan, and Can Boga. "Meningeal extramedullar haematopoiesis." British Journal of Haematology 127, no. 2 (August 12, 2004): 125. http://dx.doi.org/10.1111/j.1365-2141.2004.05136.x.
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Limaiem, Faten, Amina Mekni, Kais Nouira, Inès Chelly, Khadija Bellil, Slim Haouet, Nidhameddine Kchir, and Moncef Zitouna. "Presacral extramedullary haematopoiesis." Pathology 41, no. 3 (April 2009): 302–3. http://dx.doi.org/10.1080/00313020902756337.
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Mubarak, V., S. Fanning, M. Windsor, E. Duhig, and S. Bowler. "Pulmonary extramedullary haematopoiesis." Case Reports 2011, dec02 1 (December 2, 2011): bcr0620114392. http://dx.doi.org/10.1136/bcr.06.2011.4392.
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Arjun, Padmanabhan, and Mathew Thomas. "Intrathoracic extramedullary haematopoiesis." Postgraduate Medical Journal 96, no. 1131 (September 11, 2019): 56. http://dx.doi.org/10.1136/postgradmedj-2019-137039.
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Old, Julie M. "Haematopoiesis in Marsupials." Developmental & Comparative Immunology 58 (May 2016): 40–46. http://dx.doi.org/10.1016/j.dci.2015.11.009.
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Grenier, Julien, Barbara Peyrard, Auria Godard, Julien Cheyrol, Thiago Trovati Maciel, Wassim El Nemer, and Maria De Grandis. "New Insights into Cellular Defects during Haematopoiesis of Sickle Cell Disease Using the Townes Mouse Model." Blood 142, Supplement 1 (November 28, 2023): 3855. http://dx.doi.org/10.1182/blood-2023-181742.
Full textAbstract:
Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β globin gene leading to the synthesis of an abnormal haemoglobin (HbS), that under low oxygen tension polymerises driving the sickling of red blood cells and reducing their lifespan. SCD is characterized by anaemia, vaso-occlusion and haemolysis, progressive multiorgan damage and increased mortality. For decades, peripheral haemolysis has been considered as the sole driver of anaemia in SCD. Recently, we have demonstrated the occurrence of ineffective erythropoiesis (IE) in SCD suggesting that anaemia can be impacted by defects of central origin and hinting to abnormalities in the haematopoietic compartment. To gain insight into SCD haematopoiesis, we investigated the haematopoietic compartment of the humanized transgenic Townes mouse model by conducting an in-depth flow cytometry-based analysis in the bone marrow (BM) and spleen, comparing SS mice to control littermates (AA and AS) at 8 and 16 weeks of age (termed 8-w and 16-w, respectively). BM and spleen are two key hematopoietic tissues in adult mice: BM is involved in maintaining homeostatic haematopoiesis and spleen responds to stress haematopoiesis. First, we assessed haematopoietic differentiation in the BM of SS, AA and AS mice. Total number of BM cells and frequency of Lin Neg and Lin NegKit Pos (LK) were identical between SS and control littermates whereas a minor increase in the percentages of Lin NegSca PosKit Pos (LSK) was observed in 16-w SS mice. Within the LSK compartment, we found a 1.81- and 2.5-fold reduction of long-term haematopoietic stem cell (lt-HSC) frequency in 8-w and 16-w SS mice, respectively (Fig1 A). HSCs differentiate into multipotent progenitors (MPPs), which have decreased self-renewal capacity and progressively engage in the megakaryocytic (MPP2), myeloid-biased (MPP3), or lymphoid-biased (MPP4) lineage. The MPP3 compartment showed a 1.6-fold increased frequency in 8-w and 16-w SS mice indicating a skewing toward myeloid cell production and the onset of extramedullary haematopoiesis as early as 8 weeks after birth (Fig1 A). Next, we analysed the downstream lineages of the committed progenitors (lymphoid, granulo-macrophagic, megakaryocytic, and erythroid) and found a 1.4 and 2.3-fold increase of th megakaryocyte-erythroid progenitor cells (MEPs) and pre-CFU-Es in 8-w and 16-w SS mice, respectively (Fig1 A,B). We assessed the potential of SS hematopoietic progenitors (HSPCs) to differentiate into myelomonocytic and erythroid lineages by performing methylcellulose colony forming unit (CFU) assays with LSK and LK cells sorted from 8-w mice. Although no difference was observed in the number and type of colonies formed in vitro from SS and control HSPCs, SS colonies were much smaller than the AA/AS ones. Furthermore, serial replating showed a phenotype of stemness exhaustion in SS mice, with a dramatic decrease in the number of colonies formed by LSK cells (27.5 SS CFUs vs 51.6 AA/AS CFUs), suggesting lower self-renewal capacities of SS HSPCs. In spleen, in addition to the expected splenomegaly of SS mice, we found a trend toward a decreased frequency of the LSK compartment and an increase of the LK compartment. There was a 2.25- and 1.42-fold increase in the percentage of MPP-2 and MPP-3 cells, respectively, and a 2.1-fold increase in the pre-CFU-Es confirming an intense splenic haematopoiesis in SS mice (Fig 1B). HSPCs are known to be retained by the BM stromal cells through the chemotactic interaction of CXCL12 and CXCR4 and the adhesive interaction of VCAM-1 and VLA-4. Measuring HSC-related cytokines in BM supernatants, we found severely diminished levels of CXCL12 in SS mice as compared to control littermates (18 pg.mL -1 in SS vs 84 pg.mL -1 in AA; N=80), suggesting HSC mobilization from the BM to the spleen with disease onset. In addition to the well-established stress erythropoiesis phenotype reported in SCD mice, our study describes cellular abnormalities in the haematopoietic compartment shedding light on potential new mechanisms that contribute to SCD pathology in relation to anaemia and bone marrow stemness.