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1
Markel, Troy A., Paul Crisostomo, Meijing Wang, Christine Herring y Daniel Meldrum. "First report of a novel and phenotypically distinct stem cell population: Neonatal stem cells". Journal of the American College of Surgeons 205, n.º 3 (septiembre de 2007): S49. http://dx.doi.org/10.1016/j.jamcollsurg.2007.06.115.
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Qu-Petersen, Zhuqing, Bridget Deasy, Ron Jankowski, Makato Ikezawa, James Cummins, Ryan Pruchnic, John Mytinger et al. "Identification of a novel population of muscle stem cells in mice". Journal of Cell Biology 157, n.º 5 (20 de mayo de 2002): 851–64. http://dx.doi.org/10.1083/jcb.200108150.
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Three populations of myogenic cells were isolated from normal mouse skeletal muscle based on their adhesion characteristics and proliferation behaviors. Although two of these populations displayed satellite cell characteristics, a third population of long-time proliferating cells expressing hematopoietic stem cell markers was also identified. This third population comprises cells that retain their phenotype for more than 30 passages with normal karyotype and can differentiate into muscle, neural, and endothelial lineages both in vitro and in vivo. In contrast to the other two populations of myogenic cells, the transplantation of the long-time proliferating cells improved the efficiency of muscle regeneration and dystrophin delivery to dystrophic muscle. The long-time proliferating cells' ability to proliferate in vivo for an extended period of time, combined with their strong capacity for self-renewal, their multipotent differentiation, and their immune-privileged behavior, reveals, at least in part, the basis for the improvement of cell transplantation. Our results suggest that this novel population of muscle-derived stem cells will significantly improve muscle cell–mediated therapies.
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Oldershaw, Rachel, W. Andrew Owens, Rachel Sutherland, Martin Linney, Rachel Liddle, Lissette Magana, Gendie E. Lash, Jason H. Gill, Gavin Richardson y Annette Meeson. "Human Cardiac-Mesenchymal Stem Cell-Like Cells, a Novel Cell Population with Therapeutic Potential". Stem Cells and Development 28, n.º 9 (mayo de 2019): 593–607. http://dx.doi.org/10.1089/scd.2018.0170.
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Hegab, Ahmed E., Vi Luan Ha, Jennifer L. Gilbert, Kelvin Xi Zhang, Stephen P. Malkoski, Andy T. Chon, Daphne O. Darmawan et al. "Novel Stem/Progenitor Cell Population from Murine Tracheal Submucosal Gland Ducts with Multipotent Regenerative Potential". STEM CELLS 29, n.º 8 (26 de julio de 2011): 1283–93. http://dx.doi.org/10.1002/stem.680.
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Termini, Christina M., Amara Pang, Michelle Li, Tiancheng Fang, Vivian Y. Chang y John P. Chute. "Syndecan-2 enriches for hematopoietic stem cells and regulates stem cell repopulating capacity". Blood 139, n.º 2 (13 de enero de 2022): 188–204. http://dx.doi.org/10.1182/blood.2020010447.
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Abstract The discovery of novel hematopoietic stem cell (HSC) surface markers can enhance understanding of HSC identity and function. We have discovered a population of primitive bone marrow (BM) HSCs distinguished by their expression of the heparan sulfate proteoglycan Syndecan-2, which serves as both a marker and a regulator of HSC function. Syndecan-2 expression was increased 10-fold in CD150+CD48–CD34–c-Kit+Sca-1+Lineage– cells (long-term HSCs [LT-HSCs]) compared with differentiated hematopoietic cells. Isolation of BM cells based solely on syndecan-2 surface expression produced a 24-fold enrichment for LT-HSCs and sixfold enrichment for α-catulin+c-kit+ HSCs, and yielded HSCs with superior in vivo repopulating capacity compared with CD150+ cells. Competitive repopulation assays revealed the HSC frequency to be 17-fold higher in syndecan-2+CD34–KSL cells compared with syndecan-2–CD34–KSL cells and indistinguishable from CD150+CD34–KSL cells. Syndecan-2 expression also identified nearly all repopulating HSCs within the CD150+CD34–KSL population. Mechanistically, syndecan-2 regulates HSC repopulating capacity through control of expression of Cdkn1c (p57) and HSC quiescence. Loss of syndecan-2 expression caused increased HSC cell cycle entry, downregulation of Cdkn1c, and loss of HSC long-term repopulating capacity. Syndecan-2 is a novel marker of HSCs that regulates HSC repopulating capacity via control of HSC quiescence.
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Wang, Yanli, Wing-Cheong Lo y Ching-Shan Chou. "Modelling stem cell ageing: a multi-compartment continuum approach". Royal Society Open Science 7, n.º 3 (marzo de 2020): 191848. http://dx.doi.org/10.1098/rsos.191848.
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Stem cells are important to generate all specialized tissues at an early life stage, and in some systems, they also have repair functions to replenish the adult tissues. Repeated cell divisions lead to the accumulation of molecular damage in stem cells, which are commonly recognized as drivers of ageing. In this paper, a novel model is proposed to integrate stem cell proliferation and differentiation with damage accumulation in the stem cell ageing process. A system of two structured PDEs is used to model the population densities of stem cells (including all multiple progenitors) and terminally differentiated (TD) cells. In this system, cell cycle progression and damage accumulation are modelled by continuous dynamics, and damage segregation between daughter cells is considered at each division. Analysis and numerical simulations are conducted to study the steady-state populations and stem cell damage distributions under different damage segregation strategies. Our simulations suggest that equal distribution of the damaging substance between stem cells in a symmetric renewal and less damage retention in stem cells in the asymmetric division are favourable strategies, which reduce the death rate of the stem cells and increase the TD cell populations. Moreover, asymmetric damage segregation in stem cells leads to less concentrated damage distribution in the stem cell population, which may be more robust to the stochastic changes in the damage. The feedback regulation from stem cells can reduce oscillations and population overshoot in the process, and improve the fitness of stem cells by increasing the percentage of cells with less damage in the stem cell population.
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Punnett, Angela Susanne. "Malignancy Following Solid Organ and Hematopoietic Stem Cell Transplantation". Oncology & Hematology Review (US) 02 (2009): 49. http://dx.doi.org/10.17925/ohr.2009.02.0.49.
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There is a growing appreciation of the increased risk for malignancy following solid organ and hematopoietic stem cell transplantation as the survival of these patient populations increases overall. The risk for malignancy is related to a complex interaction of type, degree, and duration of immunosuppression, viral status, and recipient age. Most of the malignancies documented are common in the general population but occur with increasing incidence and have significant implications for post-transplant surveillance. Post-transplant lymphoproliferative disorder is specific to the transplant population and remains a treatment challenge. The development of novel immunosuppressive agents, the use of individualized immunosuppressive regimens, and collaborative therapeutic trials are necessary to advance clinical care for these patients. This article will review the current issues around malignancy in the post-transplant patient population.
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James, J. L., D. G. Hurley, T. K. J. B. Gamage, T. Zhang, R. Vather, P. Pantham, P. Murthi y L. W. Chamley. "Isolation and characterisation of a novel trophoblast side-population from first trimester placentae". REPRODUCTION 150, n.º 5 (noviembre de 2015): 449–62. http://dx.doi.org/10.1530/rep-14-0646.
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The placenta is responsible for all nutrient and gas exchange between mother and baby during pregnancy. The differentiation of specialised placental epithelial cells called trophoblasts is essential for placental function, but we understand little about how these populations arise. Mouse trophoblast stem cells have allowed us to understand many of the factors that regulate murine trophoblast lineage development, but the human placenta is anatomically very different from the mouse, and it is imperative to isolate a human trophoblast stem cell to understand human placental development. Here we have developed a novel methodology to isolate a Hoechst side-population of trophoblasts from early gestation placentae and compared their transcriptome to differentiated trophoblast populations (cytotrophoblasts and extravillous trophoblasts) using microarray technology. Side-population trophoblasts clustered as a transcriptomically distinct population but were more closely related to cytotrophoblasts than extravillous trophoblasts. Side-population trophoblasts up-regulated a number of genes characteristic of trophectoderm and murine trophoblast stem cells in comparison to cytotrophoblasts or extravillous trophoblasts and could be distinguished from both of these more mature populations by a unique set of 22 up-regulated genes, which were enriched for morphogenesis and organ development and the regulation of growth functions. Cells expressing two of these genes (LAMA2 and COL6A3) were distributed throughout the cytotrophoblast layer at the trophoblast/mesenchymal interface. Comparisons to previously published trophoblast progenitor populations suggest that the side-population trophoblasts isolated in this work are a novel human trophoblast population. Future work will determine whether these cells exhibit functional progenitor/stem cell attributes.
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Uprety, Bhawna y Heidi Abrahamse. "Targeting Breast Cancer and Their Stem Cell Population through AMPK Activation: Novel Insights". Cells 11, n.º 3 (7 de febrero de 2022): 576. http://dx.doi.org/10.3390/cells11030576.
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Despite some significant advancements, breast cancer has become the most prevalent cancer in the world. One of the main reasons for failure in treatment and metastasis has been attributed to the presence of cancer initiating cells—cancer stem cells. Consequently, research is now being focussed on targeting cancer cells along with their stem cell population. Non-oncology drugs are gaining increasing attention for their potent anticancer activities. Metformin, a drug commonly used to treat type 2 diabetes, is the best example in this regard. It exerts its therapeutic action by activating 5′ adenosine monophosphate-activated protein kinase (AMPK). Activated AMPK subsequently phosphorylates and targets several cellular pathways involved in cell growth and proliferation and the maintenance of stem-like properties of cancer stem cells. Therefore, AMPK is emerging as a target of choice for developing effective anticancer drugs. Vanadium compounds are well-known PTP inhibitors and AMPK activators. They find extensive applications in treatment of diabetes and obesity via PTP1B inhibition and AMPK-mediated inhibition of adipogenesis. However, their role in targeting cancer stem cells has not been explored yet. This review is an attempt to establish the applications of insulin mimetic vanadium compounds for the treatment of breast cancer by AMPK activation and PTP1B inhibition pathways.
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Boesch, Maximilian, Dominik Wolf y Sieghart Sopper. "Optimized Stem Cell Detection Using the DyeCycle-Triggered Side Population Phenotype". Stem Cells International 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/1652389.
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Tissue and cancer stem cells are highly attractive target populations for regenerative medicine and novel potentially curative anticancer therapeutics. In order to get a better understanding of stem cell biology and function, it is essential to reproducibly identify these stem cells from biological samples for subsequent characterization or isolation. ABC drug transporter expression is a hallmark of stem cells. This is utilized to identify (cancer) stem cells by exploiting their dye extrusion properties, which is referred to as the “side population assay.” Initially described for high-end flow cytometers equipped with ultraviolet lasers, this technique is now also amenable for a broader scientific community, owing to the increasing availability of violet laser-furnished cytometers and the advent of DyeCycle Violet (DCV). Here, we describe important technical aspects of the DCV-basedside population assayand discuss potential pitfalls and caveats helping scientists to establish a valid and reproducible DCV-basedside population assay. In addition, we investigate the suitability of blue laser-excitable DyeCycle dyes for side population detection. This knowledge will help to improve and standardize detection and isolation of stem cells based on their expression of ABC drug transporters.
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Rangel, Erika B., Samirah A. Gomes, Raul A. Dulce, Courtney Premer, Claudia O. Rodrigues, Rosemeire M. Kanashiro-Takeuchi, Behzad Oskouei et al. "C-Kit+Cells Isolated from Developing Kidneys Are a Novel Population of Stem Cells with Regenerative Potential". STEM CELLS 31, n.º 8 (agosto de 2013): 1644–56. http://dx.doi.org/10.1002/stem.1412.
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Zuk, Patricia A. "The Adipose-derived Stem Cell: Looking Back and Looking Ahead". Molecular Biology of the Cell 21, n.º 11 (junio de 2010): 1783–87. http://dx.doi.org/10.1091/mbc.e09-07-0589.
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In 2002, researchers at UCLA published a manuscript in Molecular Biology of the Cell describing a novel adult stem cell population isolated from adipose tissue—the adipose-derived stem cell (ASC). Since that time, the ASC has gone on to be one of the most popular adult stem cell populations currently being used in the stem cell field. With multilineage mesodermal potential and possible ectodermal and endodermal potentials also, the ASC could conceivably be an alternate to pluripotent ES cells in both the lab and in the clinic. In this retrospective article, a historical perspective on the ASC is given together with exciting new applications for the stem cell being considered today.
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Tang, Y., W. Wang y H. C. Liu. "Isolation and characterization of a novel stem cell-like population from endometrium". Fertility and Sterility 100, n.º 3 (septiembre de 2013): S391. http://dx.doi.org/10.1016/j.fertnstert.2013.07.714.
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Kotton, Darrell N., Attila J. Fabian y Richard C. Mulligan. "A novel stem-cell population in adult liver with potent hematopoietic-reconstitution activity". Blood 106, n.º 5 (1 de septiembre de 2005): 1574–80. http://dx.doi.org/10.1182/blood-2005-03-1017.
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Abstract A number of recent reports have documented that cells possessing hematopoietic-reconstitution ability can be identified and isolated from a variety of solid organs in the adult animal. In all studies to date, however, purified organ-derived stem cells demonstrate a diminished repopulating capacity relative to that of purified bone marrow–derived hematopoietic stem cells (BM HSCs). It has therefore been unclear whether organ-derived HSCs possess functional properties distinct from those of BM HSCs, or simply have not been purified to a comparable extent. Here we report the identification of a rare subset of cells in adult murine liver that possess potent blood-repopulating potential, approaching that of BM HSCs. The cells, isolated on the basis of dye-efflux activity and CD45 expression (termed CD45+ liver side population [SP] tip cells), exhibit a surface phenotype similar to that of freshly isolated BM HSCs derived from normal adult animals, but are phenotypically distinct in that they do not express the stem-cell marker c-kit. Single-cell transplantation studies indicate that CD45+ liver SP tip cells can be generated from BM HSCs, suggesting a relationship between stem-cell populations in the liver and bone marrow compartments. Overall, these studies have important implications for understanding extramedullary hematopoiesis, and may be relevant to current strategies aimed at inducing tolerance to transplanted organs.
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Momeny, Majid, Tiina Arsiola y Jukka Westermarck. "Cancer stem cell phosphatases". Biochemical Journal 478, n.º 14 (28 de julio de 2021): 2899–920. http://dx.doi.org/10.1042/bcj20210254.
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Cancer stem cells (CSCs) are involved in the initiation and progression of human malignancies by enabling cancer tissue self-renewal capacity and constituting the therapy-resistant population of tumor cells. However, despite the exhausting characterization of CSC genetics, epigenetics, and kinase signaling, eradication of CSCs remains an unattainable goal in most human malignancies. While phosphatases contribute equally with kinases to cellular phosphoregulation, our understanding of phosphatases in CSCs lags severely behind our knowledge about other CSC signaling mechanisms. Many cancer-relevant phosphatases have recently become druggable, indicating that further understanding of the CSC phosphatases might provide novel therapeutic opportunities. This review summarizes the current knowledge about fundamental, but yet poorly understood involvement of phosphatases in the regulation of major CSC signaling pathways. We also review the functional roles of phosphatases in CSC self-renewal, cancer progression, and therapy resistance; focusing particularly on hematological cancers and glioblastoma. We further discuss the small molecule targeting of CSC phosphatases and their therapeutic potential in cancer combination therapies.
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Dyall, Sheetal, Simon A. Gayther y Dimitra Dafou. "Cancer Stem Cells and Epithelial Ovarian Cancer". Journal of Oncology 2010 (2010): 1–9. http://dx.doi.org/10.1155/2010/105269.
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The cancer stem cell hypothesis is becoming more widely accepted as a model for carcinogenesis. Tumours are heterogeneous both at the molecular and cellular level, containing a small population of cells that possess highly tumourigenic “stem-cell” properties. Cancer stem cells (CSCs), or tumour-initiating cells, have the ability to self-renew, generate xenografts reminiscent of the primary tumour that they were derived from, and are chemoresistant. The characterisation of the CSC population within a tumour that drives its growth could provide novel target therapeutics against these cells specifically, eradicating the cancer completely. There have been several reports describing the isolation of putative cancer stem cell populations in several cancers; however, no defined set of markers has been identified that conclusively characterises “stem-like” cancer cells. This paper highlights the current experimental approaches that have been used in the field and discusses their limitations, with specific emphasis on the identification and characterisation of the CSC population in epithelial ovarian cancer.
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MARLEY, Stephen B. y Myrtle Y. GORDON. "Chronic myeloid leukaemia: stem cell derived but progenitor cell driven". Clinical Science 109, n.º 1 (23 de junio de 2005): 13–25. http://dx.doi.org/10.1042/cs20040336.
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The biology of CML (chronic myeloid leukaemia) has been extensively investigated as the disease is a paradigm of neoplasms induced when a translocation results in expression of a novel fusion protein, in this instance p210BCR-ABL. Although CML manifests itself principally as unregulated expansion of the myeloid lineage, the lesion is present in the stem cell population and it has long been assumed that disregulated stem cell kinetics must underlie the basic pathology of the disease. In this review, we present evidence that, in normal haemopoiesis, less primitive precursor cells retain considerable flexibility in their capacity to undergo self-renewal, allowing them to maintain lineage-specific homoeostasis without inflicting proliferative stress upon the stem cell population. This mechanism is dysregulated in CML and we have developed a self-renewal assay for CFU-GM (colony-forming unit-granulocyte/macrophage) which demonstrates that, in CML, the PI (proliferative index) of the myeloid progenitor cell population is increased. The ability to measure the PI as an endpoint of p210BCR-ABL expression gives considerable versatility to the in vitro investigation of putative therapeutic regimes in CML.
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Xiong, Jimin, Danijela Menicanin, Peter S. Zilm, Victor Marino, P. Mark Bartold y Stan Gronthos. "Investigation of the Cell Surface Proteome of Human Periodontal Ligament Stem Cells". Stem Cells International 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/1947157.
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The present study examined the cell surface proteome of human periodontal ligament stem cells (PDLSC) compared to human fibroblasts. Cell surface proteins were prelabelled with CyDye before processing to extract the membrane lysates, which were separated using 2D electrophoresis. Selected differentially expressed protein “spots” were identified using Mass spectrometry. Four proteins were selected for validation: CD73, CD90, Annexin A2, and sphingosine kinase 1 previously associated with mesenchymal stem cells. Flow cytometric analysis found that CD73 and CD90 were highly expressed by human PDLSC and gingival fibroblasts but not by keratinocytes, indicating that these antigens could be used as potential markers for distinguishing between mesenchymal cells and epithelial cell populations. Annexin A2 was also found to be expressed at low copy number on the cell surface of human PDLSC and gingival fibroblasts, while human keratinocytes lacked any cell surface expression of Annexin A2. In contrast, sphingosine kinase 1 expression was detected in all the cell types examined using immunocytochemical analysis. These proteomic studies form the foundation to further define the cell surface protein expression profile of PDLSC in order to better characterise this cell population and help develop novel strategies for the purification of this stem cell population.
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Yasumura, Yuyo, Takahiro Teshima, Tomokazu Nagashima, Takashi Takano, Masaki Michishita, Yoshiaki Taira, Ryohei Suzuki y Hirotaka Matsumoto. "Immortalized Canine Adipose-Derived Mesenchymal Stem Cells as a Novel Candidate Cell Source for Mesenchymal Stem Cell Therapy". International Journal of Molecular Sciences 24, n.º 3 (23 de enero de 2023): 2250. http://dx.doi.org/10.3390/ijms24032250.
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Mesenchymal stem cells are expected to be a cell source for stem cell therapy of various diseases in veterinary medicine. However, donor-dependent cell heterogenicity has been a cause of inconsistent therapeutic efficiency. Therefore, we established immortalized cells from canine adipose tissue-derived mesenchymal stem cells (ADSCs) to minimize cellular heterogeneity by reducing the number of donors, evaluated their properties, and compared them to the primary cells with RNA-sequencing. Immortalized canine ADSCs were established by transduction with combinations of the R24C mutation of human cyclin-dependent kinase 4 (CDKR24C), canine cyclin D1, and canine TERT. The ADSCs transduced with CDK4R24C, cyclin D1, and TERT (ADSC-K4DT) or with CDK4R24C and cyclin D1 (ADSC-K4D) showed a dramatic increase in proliferation (population doubling level >100) without cellular senescence compared to the primary ADSCs. The cell surface markers, except for CD90 of the ADSC-K4DT and ADSC-K4D cells, were similar to those of the primary ADSCs. The ADSC-K4DT and ADSC-K4D cells maintained their trilineage differentiation capacity and chromosome condition, and did not have a tumorigenic development. The ability to inhibit lymphocyte proliferation by the ADSC-K4D cells was enhanced compared with the primary ADSCs and ADSC-K4DT cells. The pathway analysis based on RNA-sequencing revealed changes in the pathways mainly related to the cell cycle and telomerase. The ADSC-K4DT and ADSC-K4D cells had decreased CD90 expression, but there were no obvious defects associated with the decreased CD90 expression in this study. Our results suggest that ADSC-K4DT and ADSC-K4D cells are a potential novel cell source for mesenchymal stem cell therapy.
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Calmeiro, João, Mylène Carrascal, Luís Mendes, Iola F. Duarte, Célia Gomes, João Serra, Amilcar Falcão, Maria Teresa Cruz y Bruno Miguel Neves. "Development of a novel dendritic cell-based immunotherapy targeting cancer stem cells." Journal of Clinical Oncology 37, n.º 15_suppl (20 de mayo de 2019): e14009-e14009. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14009.
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e14009 Background: Dendritic cells (DCs) are one of the central tools in cellular anti-tumor immunotherapy, being characterized by their capacity for acquiring and processing antigens and ability to produce strong antitumor immune responses. The production of clinical grade ex-vivo monocyte-derived DCs (Mo-DCs) is the most frequent approach for antitumor vaccines production. Recently, therapeutic resistance to radio/chemotherapy and disease recurrence was shown to be in part due to a small cancer stem cell (CSCs) population present in tumors. Methods: Here, we aim to target and eradicate CSCs by developing a novel DC-based immunotherapy vaccine for pancreatic and non-small cells lung cancer (NSCLC), comparing the loading of CSCs vs. classical tumor lysates. Results: CSCs from PANC-1 (pancreatic cancer) and A549 (NSCLC) cell lines were successfully isolated and characterized, overexpressing stem-like markers: NANOG, OCT4, SOX2 and CD133. CSCs resistance to Gemcitabine was also assessed. Before comparing the 2 types of vaccine loading, we also analyzed the impact of 3 GMP free-serum culture media on the phenotype and functional abilities of Mo-DCs. DCs cultured in X-VIVO 15 and AIM-V media show enhanced production of IL-12 and are able to induce a superior stimulation of T cells, mainly CTLs and Th1 subsets. By contrast, DCs cultured in DendriMACS are more prone to induce Treg polarization. Conclusions: Overall, our data demonstrate that blood monocytic precursors present considerable plasticity allowing a tailored differentiation of DCs just by changing the nutritive support. We also highlight the need of critically defining the culture medium to be used in DC cancer immunotherapy in order to attain desired cell characteristics and by consequent robust responses. Finally, our preliminary results indicate that loading DCs with CSCs antigens may be an effective strategy to target and destroy this resilient cancer cell population.
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Kaufman, CL, YL Colson, SM Wren, S. Watkins, RL Simmons y ST Ildstad. "Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells". Blood 84, n.º 8 (15 de octubre de 1994): 2436–46. http://dx.doi.org/10.1182/blood.v84.8.2436.2436.
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Abstract Bone marrow transplantation is an accepted therapy for hematologic malignancies, aplastic anemia, metabolic disorders, and solid tumors. However, graft-versus-host disease (GVHD) and failure of engraftment have limited the widespread application of this technology to nonmalignant disease states. The use of purified bone marrow stem cells has been suggested as an approach to promote engraftment yet avoid GVHD. Although bone marrow stem cells, purified by cell sorting, engraft and repopulate lethally irradiated genetically identical recipients, they do not engraft in major histocompatibility complex (MHC)-disparate allogeneic recipients. We report for the first time the characterization of a novel cell population of donor bone marrow origin, separate from the hematopoietic stem cell, that facilitates engraftment of purified allogeneic bone marrow stem cells in an MHC- specific fashion without causing GVHD. Although 1,000 purified stem cells (c-kit+/Sca-1+/lineage-) reliably repopulate syngeneic mouse recipients, 10 times that number do not engraft in MHC-disparate allogeneic recipients. The addition of as few as 30,000 facilitating cells (CD8+/CD45R+/TCR-) is sufficient to permit engraftment of purified stem cells in MHC-disparate recipients. The cell surface phenotype of this purified cellular population differs significantly from other characterized lineages of lymphoid or myeloid origin. Based on multiparameter rare-events cell sorting, the facilitating fraction is CD8+, CD3+, CD45R+, Thy 1+, class IIdim/intermediate but alpha beta- TCR- and gamma delta-TCR-. This cellular population comprises approximately 0.4% of the total bone marrow and is separate from the hematopoietic stem cell. The coadministration of purified facilitating cells plus stem cells to optimize engraftment yet avoid GVHD may expand the potential application of bone marrow transplantation to disease states in which the morbidity and mortality associated with conventional BMT cannot be justified.
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Kaufman, CL, YL Colson, SM Wren, S. Watkins, RL Simmons y ST Ildstad. "Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells". Blood 84, n.º 8 (15 de octubre de 1994): 2436–46. http://dx.doi.org/10.1182/blood.v84.8.2436.bloodjournal8482436.
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Bone marrow transplantation is an accepted therapy for hematologic malignancies, aplastic anemia, metabolic disorders, and solid tumors. However, graft-versus-host disease (GVHD) and failure of engraftment have limited the widespread application of this technology to nonmalignant disease states. The use of purified bone marrow stem cells has been suggested as an approach to promote engraftment yet avoid GVHD. Although bone marrow stem cells, purified by cell sorting, engraft and repopulate lethally irradiated genetically identical recipients, they do not engraft in major histocompatibility complex (MHC)-disparate allogeneic recipients. We report for the first time the characterization of a novel cell population of donor bone marrow origin, separate from the hematopoietic stem cell, that facilitates engraftment of purified allogeneic bone marrow stem cells in an MHC- specific fashion without causing GVHD. Although 1,000 purified stem cells (c-kit+/Sca-1+/lineage-) reliably repopulate syngeneic mouse recipients, 10 times that number do not engraft in MHC-disparate allogeneic recipients. The addition of as few as 30,000 facilitating cells (CD8+/CD45R+/TCR-) is sufficient to permit engraftment of purified stem cells in MHC-disparate recipients. The cell surface phenotype of this purified cellular population differs significantly from other characterized lineages of lymphoid or myeloid origin. Based on multiparameter rare-events cell sorting, the facilitating fraction is CD8+, CD3+, CD45R+, Thy 1+, class IIdim/intermediate but alpha beta- TCR- and gamma delta-TCR-. This cellular population comprises approximately 0.4% of the total bone marrow and is separate from the hematopoietic stem cell. The coadministration of purified facilitating cells plus stem cells to optimize engraftment yet avoid GVHD may expand the potential application of bone marrow transplantation to disease states in which the morbidity and mortality associated with conventional BMT cannot be justified.
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Larsson, Hans M., Francois Gorostidi, Jeffrey A. Hubbell, Yann Barrandon y Peter Frey. "Clonal, Self-Renewing and Differentiating Human and Porcine Urothelial Cells, a Novel Stem Cell Population". PLoS ONE 9, n.º 2 (26 de febrero de 2014): e90006. http://dx.doi.org/10.1371/journal.pone.0090006.
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Nordlander, Anna, Jonas Mattsson, Berit Sundberg y Suchitra Sumitran-Holgersson. "Novel Antibodies to the Donor Stem Cell Population CD34+/VEGFR-2+ Are Associated With Rejection After Hematopoietic Stem Cell Transplantation". Transplantation 86, n.º 5 (septiembre de 2008): 686–96. http://dx.doi.org/10.1097/tp.0b013e3181820333.
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Ross, Jason T. y Linheng Li. "Novel Function of FGFR1 in Hematopoietic Stem Cell Stress Response." Blood 110, n.º 11 (16 de noviembre de 2007): 2200. http://dx.doi.org/10.1182/blood.v110.11.2200.2200.
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Abstract The hematopoietic stem cell (HSC) is one of the best characterized tissue-specific stem cells in adult mammals, yet a great deal remains to be learned about the signaling pathways involved in its regulation. Fibroblast growth factors (FGFs), a large family of cytokines, and their cell-surface receptors (FGFRs) are known to play key roles in regulating cell proliferation, differentiation, and migration, both during embryonic development and in the adult. Although HSCs are known to express certain FGF pathway components, the functional significance of this is not well understood. In order to investigate the contribution of FGF signaling to HSC regulation, we generated a conditional Mx1-Cre/FGFR1fx/fx knockout mouse line. Though lacking an overt phenotype within the hematopoietic system under homeostatic conditions, these mice displayed defects in mobilization of HSCs to the peripheral circulation and spleen after myelosuppression with the chemotherapeutic agent 5-fluorouracil (5-FU), as compared to littermate controls. We are currently exploring the mechanism of this defect by directly testing the migratory ability of a population of bone marrow cells containing stem and progenitor cells. Of interest are cells from FGFR1 knockout mice that displayed defective migration toward recombinant chemokine (C-X-C motif) ligand 12 (CXCL12), indicating a link between FGF signaling and CXCL12/CXCR4-mediated chemotaxis, a process with known roles in mobilization. We competitively transplanted LSK/Flk2- cells (a population highly enriched for HSCs) from FGFR1 knockout and control mice into lethally irradiated recipients to test their repopulation ability. Our findings indicate an important role for signaling through FGFR1 in the mobilization of HSCs in mice, knowledge which may enhance clinical mobilization protocols.
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Müller-Sieburg, C. E. "Separation of pluripotent stem cells and early B lymphocyte precursors with antibody Fall-3." Journal of Experimental Medicine 174, n.º 1 (1 de julio de 1991): 161–68. http://dx.doi.org/10.1084/jem.174.1.161.
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A major goal in the study of hematopoiesis is to obtain populations of primitive stem cells, free of restricted and mature cells. We previously showed that a small population of normal bone marrow, the Thy-1loLin- cells, was highly enriched for pluripotent stem cells that repopulate lethally irradiated mice. These cells also differentiated along the B lymphocyte lineage in response to the stromal elements in Whitlock-Witte cultures. These two hematopoietic activities were entirely contained in and were enriched to similar extents in the Thy-1loLin- population. Here we show for the first time that these two activities can be resolved functionally and phenotypically. The cells that respond to the stroma in lymphoid culture are more sensitive to the cytotoxic drug 5-Fluorouracil than are stem cells. Furthermore, we have derived a new monoclonal antibody, Fall-3, that detects primitive stem cells but does not label the B cell precursor. This indicates that the small Thy-1loLin- population is heterogeneous, containing precursors restricted to the B cell lineage as well as pluripotent stem cells. Antibody Fall-3 defines a novel stem cell antigen, expressed on all primitive stem cells and thus, will be useful in the further characterization and isolation of both stem cells and B cell precursors.
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Magrath, Justin W., Alifiani B. Hartono y Sean B. Lee. "Abstract 902: Identification, characterization, and targeting of desmoplastic small round cell tumor cancer stem cell-like cells". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 902. http://dx.doi.org/10.1158/1538-7445.am2022-902.
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Abstract Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive form of pediatric cancer caused by a translocation between chromosomes 11 and 22, creating the novel EWSR1-WT1 fusion gene. Current therapy including surgery and the P6 chemotherapy regimen is insufficient, leading to a 5-year survival rate of only 15-25%. One potential explanation for this poor prognosis is the existence of a cancer stem cell (CSC) population with the ability to resist chemotherapy and cause both tumor recurrence and metastasis. While a CSC population has been identified in the closely related Ewing Sarcoma, most commonly caused by the EWSR1-FLI1 fusion gene, no CSC population has yet been identified in DSRCT. In this study, novel culture conditions were developed that enabled the formation of tumorspheres in vitro in the two commonly available DSRCT cell lines: JN-DSRCT-1 and BER-DSRCT. These novel culture conditions led to upregulation of stemness genes at the RNA and protein level including NANOG and SOX2, two genes that are associated with poor survival outcomes in TCGA sarcomas data. CCK-8 assay demonstrated an increased chemoresistance for tumorspheres versus normal adherent culture especially for doxorubicin, which was confirmed by reduction in PARP cleavage. This chemoresistance may be partially explained by a more quiescent CSC state as shown by reduced cell proliferation and a lower percentage of cells in the S and G2/M phases. However, cells grown in tumorspheres still robustly formed tumors in vivo, thus demonstrating the two hallmark CSC traits of chemoresistance and tumor formation. RNA-seq was performed to elucidate key differences between the adherent and sphere culture conditions and identify potential targets for the therapeutically important CSC-like population. Overrepresentation analysis and gene set enrichment analysis both showed upregulation of pathways related to chromatin assembly and disassembly, suggesting epigenetic changes as DSRCT cells move to a more stem-like state. RNA-seq further revealed kinases upregulated in tumorspheres including B-lymphocyte kinase (BLK) which previous studies have demonstrated is oncogenic, regulated by EWSR1-WT1, and not necessary for normal survival. BLK knockdown reduced CSC-like properties including abrogation of tumorsphere formation and reduction in the levels of SOX2 and NANOG. Together, this work for the first time identifies a CSC-like population in DSRCT and BLK as a potential DSRCT CSC target. Citation Format: Justin W. Magrath, Alifiani B. Hartono, Sean B. Lee. Identification, characterization, and targeting of desmoplastic small round cell tumor cancer stem cell-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 902.
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Chan, Charles, Ching-Cheng Chen, Daniel L. Kraft, Cynthia Luppen, Jae-Beom Kim, Anthony DeBoer, Kevin Wei Wei y Irving L. Weissman. "Identification and Isolation of the Hematopoietic Stem Cell Niche Initiating Cell Population". Blood 112, n.º 11 (16 de noviembre de 2008): 3574. http://dx.doi.org/10.1182/blood.v112.11.3574.3574.
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Abstract Introduction: Identification and understanding of the cells and processes that can generate, sustain and influence the HSC niche and hematopoiesis are critical for the development of a more comprehensive knowledge of normal hematopoiesis, stem cell homing, trafficking, differentiation and hematopoietic pathology. Growth and renewal in many tissues are initiated by stem cells, supported by the microenvironment (niche) in which they reside. While recent work has begun to describe functional interactions between stem cells and their niches, little is known about the formation of stem cell niches. Methods & Results: We established a functional, in vivo assay (via implantation of cells under the renal capsule) to isolate the determinants of hematopoietic stem cell (HSC) niche formation and activity. Using this novel assay, we show that a population of progenitor cells (CD45−Tie2-aV+CD105+Thy1.1−; CD105+Thy1−) sorted from 15.5 dpc fetal limbs and transplanted under the adult mouse renal capsule recruit host-derived vasculatures in a VEGF dependent manner, produce donor-derived ectopic bones through endochondral ossification, and generate a marrow cavity populated by host-derived long term reconstituting HSC (LT-HSC). In contrast, CD45−Tie2-aV+CD105+Thy1a+ (CD105+Thy1+) progenitors form bone that does not contain a marrow cavity. While analyzing these and other sorted populations, we did not observe any instances where niche was present without bone, suggesting that skeletal progenitors are necessary for initiating an HSC niche but osteoblasts alone cannot initiate and support niche activity. Suppression of factors important for HSC maintenance, such as steel factor (SLF), in progenitor populations prior to transplant did not alter their ability to initiate and support an HSC niche. On the other hand, suppression of factors involved in endochondral ossification, such as osterix and VEGF, inhibited niche generation. Furthermore, CD105+Thy1− progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification form only bone without marrow in our assay. Conclusions: In addition to identifying the limb-derived skeletal progenitor capable of endochondral ossification involved and the basic mechanisms of HSC niche initiation, our study provides a functional framework by which future studies on HSC-niche interactions at the cellular level can be carried out.
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Klochkova, Alena, Kishan Patel, Mary Grace Murray, Kathryn E. Hamilton y Kelly A. Whelan. "Su1116 HIGH AUTOPHAGIC VESICLE CONTENT IDENTIFIES A NOVEL ESOPHAGEAL BASAL CELL POPULATION WITH STEM CELL PROPERTIES". Gastroenterology 158, n.º 6 (mayo de 2020): S—513—S—514. http://dx.doi.org/10.1016/s0016-5085(20)31967-3.
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Xia, Pu y Xiao-Yan Xu. "Epithelial–mesenchymal transition and gastric cancer stem cell". Tumor Biology 39, n.º 5 (mayo de 2017): 101042831769837. http://dx.doi.org/10.1177/1010428317698373.
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Gastric cancer remains a big health problem in China. Gastric cancer cells contain a small subpopulation of cells that exhibit capabilities of differentiation and tumorigenicity. A putative explanation for ineffective therapy is the presence of cancer stem-like cells. Side population cells, which have cancer stem-like cells’ property, are characterized by the high efflux ability of Hoechst 33342 dye. Side population cells have been isolated from gastric cancer cell lines in previous studies. The epithelial–mesenchymal transition is very important in the invasion and metastasis of epithelial-derived cancers. More and more studies showed that gastric cancer stem-like cells possess high invasive ability and epithelial–mesenchymal transition property. A brief overview of the recent advancements in gastric cancer stem-like cells and epithelial–mesenchymal transition will be helpful for providing novel insight into gastric cancer treatment.
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Poleszczuk, Jan y Heiko Enderling. "Cancer Stem Cell Plasticity as Tumor Growth Promoter and Catalyst of Population Collapse". Stem Cells International 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/3923527.
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It is increasingly argued that cancer stem cells are not a cellular phenotype but rather a transient state that cells can acquire, either through intrinsic signaling cascades or in response to environmental cues. While cancer stem cell plasticity is generally associated with increased aggressiveness and treatment resistance, we set out to thoroughly investigate the impact of different rates of plasticity on early and late tumor growth dynamics and the response to therapy. We develop an agent-based model of cancer stem cell driven tumor growth, in which plasticity is defined as a spontaneous transition between stem and nonstem cancer cell states. Simulations of the model show that plasticity can substantially increase tumor growth rate and invasion. At high rates of plasticity, however, the cells get exhausted and the tumor will undergo spontaneous remission in the long term. In a series ofin silicotrials, we show that such remission can be facilitated through radiotherapy. The presented study suggests that stem cell plasticity has rather complex, nonintuitive implications on tumor growth and treatment response. Further theoretical, experimental, and integrated studies are needed to fully decipher cancer stem cell plasticity and how it can be harnessed for novel therapeutic approaches.
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Yin, Amy H., Sheri Miraglia, Esmail D. Zanjani, Graca Almeida-Porada, Makio Ogawa, Anne G. Leary, Johanna Olweus, John Kearney y David W. Buck. "AC133, a Novel Marker for Human Hematopoietic Stem and Progenitor Cells". Blood 90, n.º 12 (15 de diciembre de 1997): 5002–12. http://dx.doi.org/10.1182/blood.v90.12.5002.
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Abstract AC133 is one of a new panel of murine hybridoma lines producing monoclonal IgG antibodies (mAbs) to a novel stem cell glycoprotein antigen with a molecular weight of 120 kD. AC133 antigen is selectively expressed on CD34bright hematopoietic stem and progenitor cells (progenitors) derived from human fetal liver and bone marrow, and blood. It is not detectable on other blood cells, cultured human umbilical vein endothelial cells (HUVECs), fibroblast cell lines, or the myeloid leukemia cell line KG1a by standard flow cytometric procedures. All of the noncommitted CD34+ cell population, as well as the majority of CD34+ cells committed to the granulocytic/monocytic pathway, are stained with AC133 antibody. In vitro clonogenicity assays have demonstrated that the CD34+AC133+ double-positive population from adult bone marrow contains the majority of the CFU-GM, a proportion of the CFU-Mix, and a minor population of BFU-E. The CD34dim and AC133− population has been shown to contain the remaining progenitor cells. AC133-selected cells engraft successfully in a fetal sheep transplantation model, and human cells harvested from chimeric fetal sheep bone marrow have been shown to successfully engraft secondary recipients, providing evidence for the long-term repopulating potential of AC133+ cells. A cDNA coding for AC133 antigen has been isolated, which codes for a polypeptide consisting of 865 amino acids (aa) with a predicted size of 97 kD. This antigen is modeled as a 5-transmembrane molecule, a structure that is novel among known cell surface structures. AC133 antibody provides an alternative to CD34 for the selection and characterization of cells necessary for both short- and long-term engraftment, in transplant situations, for studies of ex vivo expansion strategies, and for gene therapy.
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Yin, Amy H., Sheri Miraglia, Esmail D. Zanjani, Graca Almeida-Porada, Makio Ogawa, Anne G. Leary, Johanna Olweus, John Kearney y David W. Buck. "AC133, a Novel Marker for Human Hematopoietic Stem and Progenitor Cells". Blood 90, n.º 12 (15 de diciembre de 1997): 5002–12. http://dx.doi.org/10.1182/blood.v90.12.5002.5002_5002_5012.
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AC133 is one of a new panel of murine hybridoma lines producing monoclonal IgG antibodies (mAbs) to a novel stem cell glycoprotein antigen with a molecular weight of 120 kD. AC133 antigen is selectively expressed on CD34bright hematopoietic stem and progenitor cells (progenitors) derived from human fetal liver and bone marrow, and blood. It is not detectable on other blood cells, cultured human umbilical vein endothelial cells (HUVECs), fibroblast cell lines, or the myeloid leukemia cell line KG1a by standard flow cytometric procedures. All of the noncommitted CD34+ cell population, as well as the majority of CD34+ cells committed to the granulocytic/monocytic pathway, are stained with AC133 antibody. In vitro clonogenicity assays have demonstrated that the CD34+AC133+ double-positive population from adult bone marrow contains the majority of the CFU-GM, a proportion of the CFU-Mix, and a minor population of BFU-E. The CD34dim and AC133− population has been shown to contain the remaining progenitor cells. AC133-selected cells engraft successfully in a fetal sheep transplantation model, and human cells harvested from chimeric fetal sheep bone marrow have been shown to successfully engraft secondary recipients, providing evidence for the long-term repopulating potential of AC133+ cells. A cDNA coding for AC133 antigen has been isolated, which codes for a polypeptide consisting of 865 amino acids (aa) with a predicted size of 97 kD. This antigen is modeled as a 5-transmembrane molecule, a structure that is novel among known cell surface structures. AC133 antibody provides an alternative to CD34 for the selection and characterization of cells necessary for both short- and long-term engraftment, in transplant situations, for studies of ex vivo expansion strategies, and for gene therapy.
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Liu, Yuanyuan, Feifei Xiao, Bijie Yang, Zhiwei Chen, Jieping Chen y Yu Hou. "Wtapblock Cell Differentiation of Hematopoietic Stem and Progenitor Cells". Blood 136, Supplement 1 (5 de noviembre de 2020): 30. http://dx.doi.org/10.1182/blood-2020-137027.
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Wilms' tumor 1-associating protein (WTAP) is a ubiquitously expressed nuclear protein has been associated with regulation of cell proliferation, apoptosis, embryonic development, cell cycle, RNA splicing and stabilization, N6-Methyladenosine RNA modification in various physiological processes. Recently,WTAPwas reported to promoter tumorigenicity in Glioblastoma and cholangiocarcinoma. Besides solid tumors,WTAPplays an important role in abnormal proliferation and arrested differentiation in acute myeloid leukemia (AML) cell, suggesting its oncogenic activity. For its promising novel therapeutic target in AML, a systematic investigation of the roles ofWTAPin normal hematopoiesis is warranted.To investigate the function ofWTAPin normal hematopoietic system, we firstly determined the mRNA level ofWTAPin different hematopoietic stem and progenitor cells (HSPCs) and several mature populations in C57/B6 mouse bone marrow (BM).WTAPwas ubiquitously expressed in different cell populations and especially elevated in HSPCs. For WTAP-null and heterozygous caused early embryonic lethality, we generated endothelial system conditional knockout (cKO) mice by crossing WTAP floxed mice with poly (I:C) induced Mx1-Cre transgenic mice. In poly (I:C) inducedWTAPfl/fl-Mx1-Cre, WTAP deficiency lead to approximately 2-fold increase in HSC and LSK pool size, and modest expansion of HPC, CLP and LMPP population. In competitive BM transplantation assay, lossWTAPshowed a significantly decreased repopulation capacity. WhileWTAPknockout did not significantly affect the proliferation, cell cycle and apoptosis of HSPCs tested by Brdu, Ki67 and Annexin-V straining assay. Mechanistically, deletion ofWTAPin HSC resulted in decreased transcription of myeloid cell and erythrocyte differentiation gene (including Jak3, Jun and Junb) and genes regulating pluripotency of stem cells (induding Akt2, Fzd1/9 and Mapk3).Collectively, we speculateWTAPplay important role in blocking cell differentiation of HSPCs. Currently, we are conducting a series of studies to reveal the underlying molecular mechanism(s) ofWTAPregulating normal hematopoiesis. Disclosures No relevant conflicts of interest to declare.
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Sommarin, Mikael, Parashar Dhapola, Linda Geironson Ulfsson, Fatemeh Safi, Eva Erlandsson, Anna Konturek, Ram Krishna Thakur, Charlotta Boiers, David Bryder y Göran Karlsson. "Immunophenotypic- and Molecular Analysis of Human Hematopoietic Stem and Progenitor Heterogeneity". Blood 134, Supplement_1 (13 de noviembre de 2019): 3701. http://dx.doi.org/10.1182/blood-2019-126407.
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Hematopoietic stem cells (HSCs) have the capacity to differentiate into all hematopoietic lineages and at the same time self-renew to maintain the HSC pool. HSCs have been thoroughly investigated using immunophenotypic-, molecular- and functional-analysis resulting in the development of protocols for high-purity prospective isolation of human HSCs. However, within the current state-of-the-art HSC populations, 90% of the cells lack stem cell activity, confounding molecular analysis of HSC function. Thus, identification of novel immunophenotypic markers to delineate the HSC population would improve our understanding of HSC biology. To identify cell-surface markers with the potential to discriminate between functionally different cells within the HSC population, we performed antibody screens measuring the expression of 340 markers on human cord blood (CB) and bone marrow (BM). Candidate markers that divide the HSC population were included in single-cell CITE-seq experiments together with conventional HSC and progenitor markers for combined analysis of immunophenotype and RNA sequencing. This allowed us to correlate the molecular signature of each single-cell with the expression of 40 cell-surface proteins in CD34+ and CD34+CD38- populations of fetal liver (FL), CB, young- and old BM. Following sequencing, the cells were clustered based on molecular signature. Fourteen distinct groups with HSC-, multipotent progenitor-, and early committed progenitor profiles were identified. To investigate how the molecularly defined groups correlate to established populations within CD34+ HSPCs, the surface marker expression from the CITE-seq experiment was included in the analysis. The immunophenotypically defined GMP, MEP and CMP populations showed high molecular heterogeneity with cells at different stages of differentiation. The immunophenotypic HSCs (CD38-CD90+CD45RA-) correlated with the molecularly defined HSC population with a 75.6% overlap. To find novel surface markers for prospective isolation of HSCs pseudo-time analysis was used, allowing for correlation of surface marker expression with differentiation status. Interestingly, both CD35 and CD11a correlated with differentiation, with CD35 expression decreasing and CD11a expression increasing with pseudo-time. These two novel HSC marker-candidates are currently being functionally validated by transplantation analysis. To compare the progenitor composition of CD34+ HSPCs at different stages of life, young BM was used as a baseline control. Interestingly, compared to young BM CB CD34+ cells contained a higher frequency of multipotent progenitor cells and a decreased proportion of committed progenitors. In contrast, old CD34+ BM was reduced in multipotent progenitor frequencies with a corresponding relative increase of committed progenitors. However, both CB and old BM showed similar proportions of molecularly defined HSCs as compared to young BM. These results indicate that ageing causes a depletion of the earliest hematopoietic progenitor populations while the HSC pool remains intact. Together, using single cell CITE-seq we can describe the immunophenotypic- and molecular-heterogeneity of the HSC and progenitor populations and identify two novel cell-surface marker candidates for prospective isolation of HSCs. Disclosures No relevant conflicts of interest to declare.
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Oakley, Erin J. y Gary Van Zant. "Identification of a Novel Candidate Regulator of HSC Aging." Blood 108, n.º 11 (16 de noviembre de 2006): 1345. http://dx.doi.org/10.1182/blood.v108.11.1345.1345.
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Abstract It is well documented that both quantitative and qualitative changes in the murine hematopoietic stem cell (HSC) population occur with age. In mice, the effect of aging on stem cells is highly strain-specific, thus suggesting genetic regulation plays a role in HSC aging. We have previously mapped a quantitative trait locus (QTL) to murine Chr 2 that is associated with the variation in frequency of HSCs between aged B6 and D2 mice. In C57BL/6 (B6) mice the HSC population steadily increases with age, whereas in DBA/2 mice, this population declines. A QTL regulating the natural variation in lifespan between the two strains was mapped to the same location on mouse Chr 2, thus leading to the hypothesis that stem cell function affects longevity. B6 alleles, associated with expansion of the stem cell pool, are also associated with a ~50% increase in lifespan. Using a congenic mouse model, in which D2 alleles in the QTL interval were introgressed onto a B6 background, genome wide gene expression analyses were performed using sorted lineage negative hematopoietic cells, which are enriched for primitive stem and progenitor cells. Three variables were examined using Affymetrix M430 arrays:the effect of strain--congenic versus background;the effect of age--2 months versus 22 months; andthe effects of 2 Gy of radiation because previous studies indicated that congenic animals were highly sensitive to the effects of mild radiation compared to B6 background animals. Extensive analysis of the expression arrays pointed to a single strong candidate, the gene encoding ribosome binding protein 1 (Rrbp1). Real-time PCR was used to validate the differential expression of Rrbp1 in lineage negative, Sca-1+, c-kit+ (LSK) cells, a population highly enriched for stem and progenitor cells. Further analysis revealed the presence eight non-synonymous, coding single nucleotide polymorphisms (SNPs), and at least one of them because of its location and nature may significantly alter protein structure and function. The Rrbp1 gene consists of 23 exons in mouse and is highly conserved among mammalian species including mouse, human, and canine. The Rrbp1 protein is present on the surface of the rough endoplasmic reticulum where it tethers ribosomes to the membrane, stabilizes mRNA transcripts, and mediates translocation of nascent proteins destined for the cell secretory pathway. It is well established that the interaction of HSCs with microenvironmental niches in the bone marrow is crucial for their maintenance and self-renewal, and that this interaction is mediated in part by the molecular repertoires displayed on the cell surfaces of both HSCs and niche stromal cells. Therefore, we hypothesize that age and strain specific variation in Rrbp1, through its role in the secretory pathway, affects the molecular repertoire at the cell surface of the HSC, thus altering the way stem cells interact with their niches. This altered microenvironmental interaction could have profound effects on fundamental properties relevant to stem cell aging such as pluripotency, self-renewal, and senescence.
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Kang, Jun, Wenguo Fan, Qianyi Deng, Hongwen He y Fang Huang. "Stem Cells from the Apical Papilla: A Promising Source for Stem Cell-Based Therapy". BioMed Research International 2019 (29 de enero de 2019): 1–8. http://dx.doi.org/10.1155/2019/6104738.
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Stem cells are biological cells that can self-renew and can differentiate into multiple cell lineages. Stem cell-based therapy is emerging as a promising alternative therapeutic option for various disorders. Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are isolated from various tissues and can be used as an alternative to embryonic stem cells. Stem cells from the apical papilla (SCAPs) are a novel population of MSCs residing in the apical papilla of immature permanent teeth. SCAPs present the characteristics of expression of MSCs markers, self-renewal, proliferation, migration, differentiation, and immunosuppression, which support the application of SCAPs in stem cell-based therapy, including the immunotherapy and the regeneration of dental tissues, bone, neural, and vascular tissues. In view of these properties and therapeutic potential, SCAPs can be considered as promising candidates for stem cell-based therapy. Thus the aim of our review was to summarize the current knowledge of SCAPs considering isolation, characterization, and multilineage differentiation. The prospects for their use in stem cell-based therapy were also discussed.
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Zhang, Bin, Rui Liu, Dan Shi, Xingxia Liu, Yuan Chen, Xiaowei Dou, Xishan Zhu et al. "Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2–dependent regulatory dendritic cell population". Blood 113, n.º 1 (1 de enero de 2009): 46–57. http://dx.doi.org/10.1182/blood-2008-04-154138.
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Abstract Mesenchymal stem cells (MSCs), in addition to their multilineage differentiation, exert immunomodulatory effects on immune cells, even dendritic cells (DCs). However, whether they influence the destiny of full mature DCs (maDCs) remains controversial. Here we report that MSCs vigorously promote proliferation of maDCs, significantly reduce their expression of Ia, CD11c, CD80, CD86, and CD40 while increasing CD11b expression. Interestingly, though these phenotypes clearly suggest their skew to immature status, bacterial lipopolysaccharide (LPS) stimulation could not reverse this trend. Moreover, high endocytosic capacity, low immunogenicity, and strong immunoregulatory function of MSC-treated maDCs (MSC-DCs) were also observed. Furthermore we found that MSCs, partly via cell-cell contact, drive maDCs to differentiate into a novel Jagged-2–dependent regulatory DC population and escape their apoptotic fate. These results further support the role of MSCs in preventing rejection in organ transplantation and treatment of autoimmune disease.
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Beyth, Shaul, Zipora Borovsky, Dror Mevorach, Meir Liebergall, Zulma Gazit, Hadi Aslan, Eithan Galun y Jacob Rachmilewitz. "Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness". Blood 105, n.º 5 (1 de marzo de 2005): 2214–19. http://dx.doi.org/10.1182/blood-2004-07-2921.
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AbstractInfusion of either embryonic or mesenchymal stem cells prolongs the survival of organ transplants derived from stem cell donors and prevents graft-versus-host-disease (GVHD). An in-depth mechanistic understanding of this tolerization phenomenon could lead to novel cell-based therapies for transplantation. Here we demonstrate that while human mesenchymal stem cells (hMSCs) can promote superantigen-induced activation of purified T cells, addition of antigen-presenting cells (APCs; either monocytes or dendritic cells) to the cultures inhibits the T-cell responses. This contact- and dose-dependent inhibition is accompanied by secretion of large quantities of interleukin (IL)–10 and aberrant APC maturation, which can be partially overridden by the addition of factors that promote APC maturation (ie, lipopolysaccharide [LPS] or anti-CD40 monoclonal antibody [mAb]). Thus, our data support an immunoregulatory mechanism wherein hMSCs inhibit T cells indirectly by contact-dependent induction of regulatory APCs with T-cell–suppressive properties. Our data may reveal a physiologic phenomenon whereby the development of a distinct APC population is regulated by the tissue's cellular microenvironment.
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Tang, Carol, Constance LM Chua y Beng-Ti Ang. "Insights into the Cancer Stem Cell Model of Glioma Tumorigenesis". Annals of the Academy of Medicine, Singapore 36, n.º 5 (15 de mayo de 2007): 352–57. http://dx.doi.org/10.47102/annals-acadmedsg.v36n5p352.
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Not all cancer cells are born equal. While the great majority of the cells that make up tumours are destined to differentiate, albeit aberrantly, and eventually stop dividing, a handful of cancer cells appear to possess limitless replicative potential. This review presents compelling evidence to suggest that the bulk of malignant cells of most cancers are generated by a rare fraction of stem cell-like cancer cells. These cells, dubbed cancer stem cells, are phenotypically similar to the normal stem cells of the corresponding tissue of origin, but they exhibit dysfunctional patterns of self-renewal and differentiation. Cancer stem cells that are capable of recapitulating brain tumours as xenografts in mice are characterised by defined stem cell markers. These brain tumour stem cells demonstrate enhanced chemoresistance and radioresistance mechanisms compared to non-stem cells in the heterogeneous tumour, which suggest that they may be the likely candidates for tumour progression and recurrence. Indeed, recent work has shown that such aberrant signalling pathways may be targeted in novel anti-cancer therapeutic strategies. The stem cell concept of tumour progression prompts immediate attention to a new paradigm in cancer research with a focus on this minority subset of cells, and the design of novel therapeutic strategies to target these cells that are insignificant within the population of tumour cells, but that are in fact the relevant cells to be destroyed. Key words: Cancer stem cell, CD133, Side population, Serial transplantation
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Potez, Marine, Sebastian Snedal, Jongmyung Kim, Konrad Thorner, Maria Cecilia Ramello, Daniel Abate-Daga y James Liu. "STEM-14. GLIOBLASTOMA STEM CELL TARGETING CHIMERIC ANTIGEN RECEPTOR T CELLS MODIFIED USING PHAGE DISPLAY ISOLATED PEPTIDES". Neuro-Oncology 22, Supplement_2 (noviembre de 2020): ii199. http://dx.doi.org/10.1093/neuonc/noaa215.831.
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Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with high mortality rates and resistance to conventional therapy. Their resistance to conventional therapy has been attributed to the presence of cancer stem cells (CSCs), a sub-population of tumor cells capable of self-renewal and tumor initiation. Developing novel strategies to specifically target GSCs may allow more effective therapeutic strategies. Using in vivo phage display biopanning, we have identified several peptides with the potential to selectively target and bind GSCs. We wished to leverage the GSC targeting properties of the peptides to augment therapeutic delivery vehicles for the development of novel targeting strategies. We used a combination of GSC targeting peptides to modify the antigen-binding domain of chimeric antigen receptors, by arranging the peptides in tandem at the N-terminus of the CAR molecule. These tandem peptides were tested for binding to GSCs in vitro and in vivo. The functionality of the CAR-T cells was evaluated by measuring cytokine release in the supernatant after overnight co-culture through ELISA. Apoptosis was evaluated by flow cytometry with Annexin V staining. Two different GSC-targeting peptide CAR-T cells demonstrated specific targeting GSCs. Following co-culture with GSCs, GSC targeting CAR-T cells were activated with release of Interferon gamma and subsequently induced GSCs specific apoptosis. These results demonstrate the use of phage display biopanning to isolate GSC targeting peptides which may be used to develop novel GBM specific cytotoxic therapies.
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Carrieri, Claudia, Stefano Comazzetto, Amit Grover, Marcos Morgan, Andreas Buness, Claus Nerlov y Dónal O’Carroll. "A transit-amplifying population underpins the efficient regenerative capacity of the testis". Journal of Experimental Medicine 214, n.º 6 (1 de mayo de 2017): 1631–41. http://dx.doi.org/10.1084/jem.20161371.
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The spermatogonial stem cell (SSC) that supports spermatogenesis throughout adult life resides within the GFRα1-expressing A type undifferentiated spermatogonia. The decision to commit to spermatogenic differentiation coincides with the loss of GFRα1 and reciprocal gain of Ngn3 (Neurog3) expression. Through the analysis of the piRNA factor Miwi2 (Piwil4), we identify a novel population of Ngn3-expressing spermatogonia that are essential for efficient testicular regeneration after injury. Depletion of Miwi2-expressing cells results in a transient impact on testicular homeostasis, with this population behaving strictly as transit amplifying cells under homeostatic conditions. However, upon injury, Miwi2-expressing cells are essential for the efficient regenerative capacity of the testis, and also display facultative stem activity in transplantation assays. In summary, the mouse testis has adopted a regenerative strategy to expand stem cell activity by incorporating a transit-amplifying population to the effective stem cell pool, thus ensuring rapid and efficient tissue repair.
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Zhang, Yuan, Priyadharshini Sivakumaran, Andrew E. Newcomb, Damián Hernandez, Nicole Harris, Ramin Khanabdali, Guei-Sheung Liu et al. "Cardiac Repair With a Novel Population of Mesenchymal Stem Cells Resident in the Human Heart". STEM CELLS 33, n.º 10 (29 de julio de 2015): 3100–3113. http://dx.doi.org/10.1002/stem.2101.
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Barkauskas, Christina E. "A Specialized Few Among Many: Identification of a Novel Lung Epithelial Stem Cell Population". Cell Stem Cell 26, n.º 3 (marzo de 2020): 295–96. http://dx.doi.org/10.1016/j.stem.2020.02.010.
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Klochkova, Alena, Adam Karami, Louis Parham, Mary Grace Murray, Kathryn E. Hamilton y Kelly A. Whelan. "964: HIGH AUTOPHAGIC VESICLE CONTENT IDENTIFIES A NOVEL SLOWCYCLING ESOPHAGEAL BASAL CELL POPULATION WITH STEM CELL PROPERTIES". Gastroenterology 162, n.º 7 (mayo de 2022): S—226. http://dx.doi.org/10.1016/s0016-5085(22)60543-2.
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Golubeva, Vera, Juliana Mikhalevich, Julia Novikova, Olga Tupizina, Svetlana Trofimova y Yekaterina Zueva. "Novel cell population data from a haematology analyzer can predict timing and efficiency of stem cell transplantation". Transfusion and Apheresis Science 50, n.º 1 (febrero de 2014): 39–45. http://dx.doi.org/10.1016/j.transci.2013.12.004.
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Kumar, Harish, Ujjal Kumar Mukherjee, Suman Mazumder, Sabyasachi Sanyal, Brian G. Van Ness y Amit Kumar Mitra. "Repurposing Clofazimine As a Novel Drug for the Treatment of PI-Resistant Stem Cell-like Subclones in Myeloma". Blood 134, Supplement_1 (13 de noviembre de 2019): 4418. http://dx.doi.org/10.1182/blood-2019-131596.
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Multiple myeloma (MM) is the second-most common hematopoietic malignancy in the United States with estimated new reported cases of 32,110 and deaths of 12,960 in 2019. Despite recent improvement in therapies, including proteasome inhibitors (PIs) - the standard-of-care drug, MM still remains a difficult-to-cure disease with significant complexity and heterogeneity at the molecular level. Recent studies have shown that the presence of cell sub populations with potential cancer stem cell-like properties (MM-CSCs), including CD19- CD138- quiescent stem cells, dormant cells, ALDH+ cells and side populations/SP, in drug-resistant tumors significantly contribute to the development of PI resistance in myeloma. However, no study so far has attempted to develop drugs specifically targeting MM-CSCs involved in drug resistance. Further, the gene signature underlying these sub cellular populations are yet to be revealed. We have previously demonstrated that Clofazimine (CFZ), an anti-leprosy drug, could be successfully repurposed for the treatment of Chronic myeloid leukemia (CML) by specifically targeting quiescent stem cell population (CD34+CD38-, CFSE-bright) in drug resistant patient samples. Here, we hypothesized that we will repurpose CFZ as a novel drug for the treatment of PI-resistant MM by targeting the sub-cellular stem cell-like subclones. Therefore, in the current study we utilized our panel of >50 human myeloma cell lines (HMCLs) representing innate PI-response/resistance and >10 pairs (parental and PI-resistant lines generated using dose escalation over a period of time) of clonally derived PI-resistant HMCLs representing acquired resistance to repurpose CFZ for the management of PI-resistant MM. Cells were treated with CFZ and the PIs Bortezomib (Bz), Carfilzomib (Cz), Ixazomib (Ix) and Oprozomib (Opz) as single agents or in combination and in vitro cytotoxicity was determined using CellTiter-Glo assay. Synergy between CFZ and PIs was analyzed by Calcusyn software based on Chou-Talalay's combination index (CI) theorem. Drug-induced apoptosis, ROS generation, mitochondrial membrane potential and cell cycle arrest were evaluated by Flow cytometry. Sub-cellular stem cell-like populations were isolated using cell sorting by Flow Cytometry (FCM/FACS). Tumorigenic potential of purified MM-CSCs was determined using colony forming assay, carboxyfluorescein succinimidyl ester (CFSE) assay, Aldeflour activity and analysis of side population in resistant MM cells. We found very promising preliminary results where CFZ alone showed very potent inhibition of cell viability in HMCLs. Further, treatment with CFZ + PIs significantly improved the therapeutic index of PI administration to the cells. Similar results were observed in parental (P) vs clonally derived PI-resistant (VR) cell lines. We next evaluated if CFZ alone or in combination with PIs could erode quiescent CD138+ cells in parental-P/clonally derived PI-resistant cells-VR. Hence, we labelled RPMI-8226 (parental cells), RPMI8226-VR with CFSE and treated them with drugs for 96h. While PIs failed to reduce CFSE-bright (non-dividing) cells, CFZ alone or in combination with Ixazomib significantly reduced their number and increased CFSE-dim (dividing cell) population. Evaluation of apoptosis in these cells revealed that CFZ alone caused apoptosis in both CFSE-bright and CFSE-dim cells while combining CFZ +PI caused a more robust effect amounting to their near-obliteration. We next assessed side populations/SP in resistant cells. We found that % SP was higher in resistant cells as compared to parental cells. CFZ alone or in combination (CFZ+PI) reduced %SP in PI- resistant cell lines. Based on these results, we propose that CFZ may have strong potential to increase the therapeutic efficacy of PIs when used in combination by specifically targeting MM-CSCs sub cellular population in MM - which we are investigating further. Currently, we are: 1) validating the potency of CFZ (alone or CFZ+PI combination therapy) in primary myeloma cells/PMCs from newly diagnosed patients, followed by 2) bulk mRNA sequencing and 3) single-cell transcriptomic analysis of MM-CSCs in HMCLs and PMCs to evaluate molecular pathways involved in stem-cell based PI-resistance and to characterize PI-resistant sub-cellular stem cell populations based on gene expression signatures using our prediction analysis software SCATTome. Disclosures No relevant conflicts of interest to declare.
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Zabierowski, Susan E. y Meenhard Herlyn. "Melanoma Stem Cells: The Dark Seed of Melanoma". Journal of Clinical Oncology 26, n.º 17 (10 de junio de 2008): 2890–94. http://dx.doi.org/10.1200/jco.2007.15.5465.
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Cells with stem-cell markers and features have recently been identified in melanoma tissues and cell lines. Melanoma stem-like cells possess many traits of tumor-initiating or tumor stem cells including self-renewal capacity, high tumorigenicity, and differentiation into various mesenchymal lineages, including melanocytic cells. Four subpopulations of melanoma-initiating cells have been distinguished: CD20+, CD133+, label-retaining or slow-cycling cells, and side-population cells with high efflux activities. Whether these are distinct or overlapping populations is currently under investigation. Ongoing studies are dissecting and characterizing the hierarchy of these subpopulations within a malignant lesion. Understanding these and the dynamics of clonal dominance will aid in the development of novel therapeutic strategies.
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Cox, Benoit, Emma Laporte, Annelies Vennekens, Hiroto Kobayashi, Charlotte Nys, Indra Van Zundert, Hiroshi Uji-i et al. "Organoids from pituitary as a novel research model toward pituitary stem cell exploration". Journal of Endocrinology 240, n.º 2 (febrero de 2019): 287–308. http://dx.doi.org/10.1530/joe-18-0462.
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The pituitary is the master endocrine gland, harboring stem cells of which the phenotype and role remain poorly characterized. Here, we established organoids from mouse pituitary with the aim to generate a novel research model to study pituitary stem cell biology. The organoids originated from the pituitary cells expressing the stem cell marker SOX2 were long-term expandable, displayed a stemness phenotype during expansive culture and showed specific hormonal differentiation ability, although limited, after subrenal transplantation. Application of the protocol to transgenically injured pituitary harboring an activated stem cell population, resulted in more numerous organoids. Intriguingly, these organoids presented with a cystic morphology, whereas the organoids from undamaged gland were predominantly dense and appeared more limited in expandability. Transcriptomic analysis revealed distinct epithelial phenotypes and showed that cystic organoids more resembled the pituitary phenotype, at least to an immature state, and displayed in vitro differentiation, although yet moderate. Organoid characterization further exposed facets of regulatory pathways of the putative stem cells of the pituitary and advanced new injury-activated markers. Taken together, we established a novel organoid research model revealing new insights into the identity and regulation of the putative pituitary stem cells. This organoid model may eventually lead to an interesting tool to decipher pituitary stem cell biology in both healthy and diseased gland.
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Dollé, Laurent, Luke Boulter, Isabelle A. Leclercq y Leo A. van Grunsven. "Next generation of ALDH substrates and their potential to study maturational lineage biology in stem and progenitor cells". American Journal of Physiology-Gastrointestinal and Liver Physiology 308, n.º 7 (1 de abril de 2015): G573—G578. http://dx.doi.org/10.1152/ajpgi.00420.2014.
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High aldehyde dehydrogenase (ALDH) activity is a feature of stem cells from normal and cancerous tissues and a reliable universal marker used to isolate them. There are numerous ALDH isoforms with preferred substrate specificity variably expressed depending on tissue, cell type, and organelle and cell status. On the other hand, a given substrate may be metabolized by several enzyme isoforms. Currently ALDH activity is evidenced by using Aldefluor, a fluorescent substrate likely to be metabolized by numerous ALDH isoforms. Therefore, isolation techniques based on ALDH activity detection select a heterogeneous population of stem or progenitor cells. Despite active research in the field, the precise role(s) of different ALDH isoforms in stem cells remains enigmatic. Understanding the metabolic role of different ALDH isoform in the control of stem cell phenotype and cell fate during development, tissue homeostasis, or repair, as well as carcinogenesis, should open perspectives to significant discoveries in tissue biology. In this perspective, novel ALDH substrates are being developed. Here we describe how new substrates could be instrumental for better isolation of cell population with stemness potential and for defining hierarchy of cell populations in tissue. Finally, we speculate on other potential applications.