scholarly journals Comparative RNAi Screens in Isogenic Human Stem Cells RevealSMARCA4as a Differential Regulator

2018 ◽  
Author(s):  
Ceren Güneş ◽  
Maciej Paszkowski-Rogacz ◽  
Susann Rahmig ◽  
Shahryar Khattak ◽  
Martin Wermke ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Large Scale ◽  
Model Organisms ◽  
Human Stem Cells ◽  
Cell Type ◽  
Hematopoietic Stem ◽  
Neural Lineage ◽  
Powerful Approach

SUMMARYLarge-scale RNAi screens are a powerful approach to identify functions of genes in a cell-type specific manner. For model organisms, genetically identical (isogenic) cells from different cell-types are readily available, making comparative studies meaningful. For humans, however, screening isogenic cells is not straightforward. Here, we show that RNAi screens are possible in genetically identical human stem cells, employing induced pluripotent stem cell as intermediates. The screens revealedSMARCA4(SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4) as a stemness regulator, while balancing differentiation distinctively for each cell type.SMARCA4knockdown in hematopoietic stem progenitor cells (HSPC) caused impaired self-renewalin-vitroandin-vivowith skewed myeloid differentiation; whereas in neural stem cells (NSC), it impaired selfrenewal while biasing differentiation towards neural lineage, through combinatorial SWI/SNF subunit assembly. Our findings pose a powerful approach for deciphering human stem cell biology and attribute distinct roles toSMARCA4in stem cell maintenance.

Leukemic CD34+CD38- Cells Display Conserved Differential Expression of Many ATP Binding-Cassette Transporter Genes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1380-1380
Author(s):  
Marc H.G.P. Raaijmakers ◽  
Elke P.L.M. de Grouw ◽  
Louis T.F. van de Locht ◽  
Bert A. van der Reijden ◽  
Theo J.M. de Witte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stem Cell ◽  
Abc Transporters ◽  
Cell Biology ◽  
Cell Fraction ◽  
Atp Binding ◽  
Stem Cell Biology ◽  
Hematopoietic Stem ◽  
Atp Binding Cassette

Abstract In most cases of acute myeloid leukemia (AML) CD34+CD38− cells are considered to be stem cells, responsible for the maintenance and relapse of AML. ATP binding cassette transporters function in the extrusion of xenobiotics and chemotherapeutical compounds, and may be involved in therapy resistance. Elucidation of mechanisms conferring drug resistance to CD34+CD38− cells is essential to provide novel targets for stem cell eradication in AML. We studied gene expression of all 45 transmembrane ABC transporters (the complete ABCA, B, C, D and G family) in human hematopoietic CD34+CD38− cells and more committed CD34+CD38+ progenitor cells, from healthy donors and patients with non-hematological diseases (N=11) and AML patients (N=11). Gene expression was assessed using a novel real-time RT-PCR approach with micro fluidic cards. In normal CD34+CD38− cells 36 ABC transporters were expressed, 22 of these displayed significant higher expression in the CD34+CD38− cell fraction compared to the CD34+CD38+ cell fraction. In addition to the known stem cell transporters (ABCB1, ABCC1 and ABCG2) these differential expressed genes included many members not previously associated with stem cell biology. In AML the ABC transporter expression profile was largely conserved, including expression of all 13 known drug transporters. These data suggest an important role for many ABC transporters in hematopoietic stem cell biology. In addition, the preferential expression of a high number of drug transport related transporters predicts that broad spectrum inhibition of ABC transporters is likely to be required for CD34+38− stem cell eradication in AML. This approach will, apart from affecting the leukemic stem cells, equally affect the normal stem cells.

Characterization of the Putative Stem Cells From Umbilical Cord Blood.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4231-4231
Author(s):  
Amos S. Gaikwad ◽  
Michael Cubbage ◽  
Tatiana Goltsova ◽  
Christopher Threeton ◽  
Maria Ty ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cord Blood ◽  
Cell Population ◽  
Cell Biology ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Side Population ◽  
Hematopoietic Stem ◽  
Cell Fractions

Abstract Abstract 4231 Cord blood (CB) is a rich source of hematopoietic stem cells (HSC) with long-term repopulating activity necessary for allogeneic stem cell transplantation. CD34+ stem cells are considered sufficient for transplantation, however recent progress in stem cell biology indicates that cells with other surface markers such as CD133 or cells expressing high aldehyde dehydrogenase activity with low side scatter (ALDHhigh/SSClow) or a rare side population (SP) of cells that exclude the Hoechst 33342 vital dye via multi drug transporters have been shown to possess stem cell properties. We characterized CD34+, CD133+, ALDH+ and SP in mononuclear cells (MNC) isolated from human CB. While the SP cell population is rare and detectable in few CB-MNC examined, we found abundant CD34+ and CD133+ cells (1.0+/-0.5 and 0.8+/-0.4 per 100 CD45+ MNC cells, respectively) following the ISHAGE protocol. A distinct ALDH+ cell population (median of 0.26%; range of 0.1 to 0.5%) was also present in all of the CB-MNC analyzed. Over 90% of the ALDH+ cells were also CD34+ and CD133+. The ability of CB-MNC to form colonies in methocult semi-solid media supplemented with cytokines yielded myeloid, lymphoid and erythroid colonies. The clonogenic potential of CB-MNC ranged from 16-48%. We are assessing the colony forming ability of purified stem cell fractions using flow cytometry. The clonogenic efficiency of these individual putative stem cells will be discussed. Disclosures: No relevant conflicts of interest to declare.

The Role of Nucleophosmin In Hematopoietic Stem Cells and the Pathogenesis of Myelodysplastic Syndrome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 95-95 ◽  
Author(s):  
Keisuke Ito ◽  
Paolo Sportoletti ◽  
John G Clohessy ◽  
Grisendi Silvia ◽  
Pier Paolo Pandolfi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Cell Biology ◽  
De Novo ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

Abstract Abstract 95 Myelodysplastic syndrome (MDS) is an incurable stem cell disorder characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Nucleophosmin (NPM) is directly implicated in primitive hematopoiesis, the pathogenesis of hematopoietic malignancies and more recently of MDS. However, little is known regarding the molecular role and function of NPM in MDS pathogenesis and in stem cell biology. Here we present data demonstrating that NPM plays a critical role in the maintenance of hematopoietic stem cells (HSCs) and the transformation of MDS into leukemia. NPM is located on chromosome 5q and is frequently lost in therapy-related and de novo MDS. We have previously shown that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment and Npm1+/− mice develop a hematologic syndrome with features of human MDS, including increased susceptibility to leukemogenesis. As HSCs have been demonstrated to be the target of the primary neoplastic event in MDS, a functional analysis of the HSC compartment is essential to understand the molecular mechanisms in MDS pathogenesis. However, the role of NPM in adult hematopoiesis remains largely unknown as Npm1-deficiency leads to embryonic lethality. To investigate NPM function in adult hematopoiesis, we have generated conditional knockout mice of Npm1, using the Cre-loxP system. Analysis of Npm1 conditional mutants crossed with Mx1-Cre transgenic mice reveals that Npm1 plays a crucial role in adult hematopoiesis and ablation of Npm1 in adult HSCs leads to aberrant cycling and followed by apoptosis. Analysis of cell cycle status revealed that HSCs are impaired in their ability to maintain quiescence after Npm1-deletion and are rapidly depleted in vivo as well as in vitro. Competitive reconstitution assay revealed that Npm1 acts cell-autonomously to maintain HSCs. Conditional inactivation of Npm1 leads to an MDS phenotype including a profoundly impaired ability to differentiate into cells of the erythroid lineage, megakaryocyte dyspoiesis and centrosome amplification. Furthermore, Npm1 loss evokes a p53-dependent response and Npm1-deleted HSCs undergo apoptosis in vivo and in vitro. Strikingly, transfer of the Npm1 mutation into a p53-null background rescued the apoptosis of Npm1-ablated HSCs and resulted in accelerated transformation to an aggressive and lethal form of acute myeloid leukemia. Our findings highlight the crucial role of NPM in stem cell biology and identify a new mechanism by which MDS can progress to leukemia. This has important therapeutic implications for de novo MDS as well as therapy-related MDS, which is known to rapidly evolve to leukemia with frequent loss or mutation of TRP53. Disclosures: No relevant conflicts of interest to declare.

A recessive screen for genes regulating hematopoietic stem cells

Blood ◽  
2010 ◽  
Vol 116 (26) ◽  
pp. 5849-5858 ◽  
Author(s):  
Peter Papathanasiou ◽  
Robert Tunningley ◽  
Diwakar R. Pattabiraman ◽  
Ping Ye ◽  
Thomas J. Gonda ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Biology ◽  
Regulatory Networks ◽  
Novel Mutation ◽  
Chemical Mutagenesis ◽  
Myb Transcription Factor ◽  
Cell Sorter ◽  
Hematopoietic Stem

Abstract Identification of genes that regulate the development, self-renewal, and differentiation of stem cells is of vital importance for understanding normal organogenesis and cancer; such knowledge also underpins regenerative medicine. Here we demonstrate that chemical mutagenesis of mice combined with advances in hematopoietic stem cell reagents and genome resources can efficiently recover recessive mutations and identify genes essential for generation and proliferation of definitive hematopoietic stem cells and/or their progeny. We used high-throughput fluorescence-activated cell sorter to analyze 9 subsets of blood stem cells, progenitor cells, circulating red cells, and platelets in more than 1300 mouse embryos at embryonic day (E) 14.5. From 45 pedigrees, we recovered 6 strains with defects in definitive hematopoiesis. We demonstrate rapid identification of a novel mutation in the c-Myb transcription factor that results in thrombocythemia and myelofibrosis as proof of principal of the utility of our fluorescence-activated cell sorter–based screen. Such phenotype-driven approaches will provide new knowledge of the genes, protein interactions, and regulatory networks that underpin stem cell biology.

Genome-wide association study on 13,167 individuals identifies regulators of blood CD34+ cell levels

Blood ◽  
2022 ◽  
Author(s):  
Aitzkoa Lopez de Lapuente Portilla ◽  
Ludvig Ekdahl ◽  
Caterina Cafaro ◽  
Zain Ali ◽  
Natsumi Miharada ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Association Study ◽  
Drug Targets ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Myb Transcription Factor ◽  
Hematopoietic Stem ◽  
Genome Wide

Stem cell transplantation is a cornerstone in the treatment of blood malignancies. The most common method to harvest stem cells for transplantation is by leukapheresis, requiring mobilization of CD34+ hematopoietic stem and progenitor cells (HSPC) from the bone marrow into the blood. Identifying the genetic factors that control blood CD34+ cell levels could expose new drug targets for HSPC mobilization. Here, we report the first large-scale genome-wide association study on blood CD34+ cell levels. Across 13,167 individuals, we identify 9 significant and 2 suggestive associations, accounted for by 8 loci (PPM1H, CXCR4, ENO1-RERE, ITGA9, ARHGAP45, CEBPA, TERT and MYC). Notably, 4 of the identified associations map to CXCR4, demonstrating that bona fide regulators of blood CD34+ cell levels can be identified through genetic variation. Further, the most significant association maps to PPM1H, encoding a serine/threonine phosphatase never previously implicated in HSPC biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. Through functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates a MYB transcription factor binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, PPM1H knockdown increases the proportion of CD34+ and CD34+90+ cells in cord blood assays. Our results provide first large-scale analysis of the genetic architecture of blood CD34+ cell levels, and warrant further investigation of PPM1H as a potential inhibition target for stem cell mobilization.

Development of a Novel NOD/SCID Transplant System That Provides Enhanced Detection of Rapid-SRC and Insight into Their Self-Renewal and Mobilization.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 249-249 ◽  
Author(s):  
Joby L. McKenzie ◽  
Olga I. Gan ◽  
Monica Doedens ◽  
John E. Dick
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Nk Cells ◽  
Cell Biology ◽  
Scid Mice ◽  
Immune Recognition ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Insight Into

Abstract The conventional NOD/SCID xenotransplant model provides a powerful tool to characterize human hematopoietic stem cells. This system relies on IV injection of transplanted cells, with subsequent circulation through the blood prior to homing to appropriate niches. Two major limitations of this model are the presence of residual host factors that resist engraftment (i.e. NK cells and macrophages) and inability to detect stem cells that are incapable of homing or surviving in the circulation. We previously showed that rapid-SRC (R-SRC) were more efficiently detected by direct intrafemoral (IF) injection compared to IV transplantation (Nat Med 2003). Additionally, others showed that depletion of NK cell activity detects a short-term repopulating cell indicating that immune recognition is also important. R-SRC are found in the Lin-CD34+CD38+/lo population and produce a robust human erythromyeloid graft 2 weeks post-transplant. R-SRC are critical for stem cell therapies that require rapid engraftment and their characterization requires an efficient assay. To determine the role of cellular resistance factors we compared human engraftment in NOD/SCID mice, NOD/SCID-B2 microglobulin-null (NOD/SCID-B2m−/−) mice that are depleted of NK cells, or we administered a neutralizing antibody against the IL-2R B-chain (CD122) to NOD/SCID mice. CD122 depletes several populations including NK cells and macrophages. 4–5 x 104 Lin-CD34+CD38lo cells purified from CB were injected IF or IV into these recipients and human engraftment was determined at 2 weeks post-transplant to assay for R-SRC. In addition to determining engraftment levels, we also used the IF assay to gain insight into migration/mobilization function of R-SRC by examining human engraftment in other bones. Human myelolymphoid (CD45+) engraftment in the injected femur (RF) was significantly higher (p<0.05) in IF injected anti-CD122 treated NOD/SCID mice compared to all other groups. Since IF NOD/SCID-B2M−/ − mice had the next highest engraftment levels, these data indicate that R-SRC are very sensitive to NK activity. However the data clearly show that CD122+ cells also play a significant role in resisting stem cell engraftment. Importantly, CD122+ cells markedly affected R-SRC migration/mobilization since there was significantly higher engraftment in non-injected bones from anti-CD122 treated mice even when compared to the NOD/SCID-B2M−/ − mice. Our previous clonal analysis showed that R-SRC that are found in non-injected bones also self-renew in the injected bone before migration. We conclude that in addition to NK cells, CD122+ cells (likely macrophages) prevent the direct engraftment of R-SRC when delivered by IF or IV injection as well as their subsequent in vivo self-renewal and/or migration. Modification to the standard NOD/SCID assay by IF injection in combination with anti-CD122 provides a powerful tool to identify novel populations of stem cells as well as insight into fundamentally important properties of stem cell biology and transplantation. Mouse (n) Injection Tissue CD45+ (%) Erythroid (CD45-CD36+glyA+ (%) Total * RF-injected rt femur;BM-noninjected lt femur, pelvis, two tibiae;glyA-glycophorinA;*-total CD45+plus CD45-erythroid engraftment NOD/SCID anti-CD122 (15) IF RF 13.2 41.4 54.6 BM 4.9 23.3 28.1 NOD/SCID anti-CD122 (18) IV RF 5.3 26.5 31.8 BM 6.6 33.5 40.1 NOD/SCID (13) IF RF 3.6 11.9 15.5 BM 0.9 2.6 3.5 NOD/SCID (15) IV RF 1.4 3.9 5.3 BM 1.3 4.2 5.5 NOD/SCID/B2M−/ − (6) IF RF 7.2 31.9 39.1 BM 1.8 7.0 8.8 NOD/SCID/B2M−/ − (9) IV RF 3.5 4.9 8.3 BM 3.4 9.4 12.8

Change in SP Distribution with Age Reflects Intrinsic Age-Based Changes in Stem Cell Biology: Implications for the Mechanism of Aging.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4209-4209
Author(s):  
Daniel J. Pearce ◽  
Catherine Simpson ◽  
Kirsty Allen ◽  
Ayad Eddaoudi ◽  
Derek Davies ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Cell Biology ◽  
Stem Cell Biology ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
The Absolute

Abstract It has been postulated that as we age, accumulated damage causes stem cells to die by apoptosis. This could lead to a diminished stem cell pool and consequently a reduced organ regeneration potential that contributes to somatic senescence. Hematopoietic stem cells have evolved many mechanisms to cope with their exposure to toxins during life. Cell surface transporters and anti-toxic enzymes are highly expressed in hematopoietic stem cells. If toxins do get the opportunity to damage the DNA of stem cells then the cell is more likely to die by apoptosis than attempt DNA repair and risk an error. Summarised below are our results from an investigation of the frequency, phenotype, cell cycle status and repopulation potential (in young recipients) of C57BL6 side population (SP) cells from mice with a range of ages. The absolute frequency of SP cells increases with age (Figure-A). The proportion of the lineage negative, Sca-1+, c-kit+ (KLS) cell population that is an SP stem cell increases from ~1% to over 30% during the murine lifetime (red bars in Figure-B). These SP cells from older mice have a reduced 4-month competitive repopulation potential when compared to SP cells from younger mice but contain a similarly low proportion of phenotypically-defined mature cells (blue bars in Figure-B) and have a similar cell cycle profile and progenitor cell output (2% of 3 x 96 well plates for each). SP cells from older mice contained a higher proportion of SP cells with the highest efflux ability (61 vs 414 days, p=<0.001, n=6) Engrafted cells derived from old SP cells 4 months previously still displayed an increased SP frequency when compared to engrafted cells derived from SP cells of young mice. Hence, more progenitors or committed cells have not gained the SP ability; rather this difference in SP distribution reflects an age-dependent change in hematopoietic stem cell biology that is independent of the microenvironment. Specifically, the proportion of stem and progenitor cells (KLS) that is a stem cell (SP fraction of KLS) increases with age. We hypothesize that this may be a progressive enrichment of primitive cells over time via selection. As we age, accumulative damage to hematopoietic stem and progenitor cells causes more cells to die by apoptosis. It may be that the stem/progenitor cells with the lowest hoechst efflux ability are most susceptible to damage and hence most likely to die by apoptosis. Since the HSCs with the highest efflux of hoechst are thought to be the most primitive, it may be that there is an enrichment of primitive cells. This could account for the increased SP proportion observed within KLS cells. As there may be cells with ABC/G2 activity that is undetectable via the SP technique, selection of cells with a higher pump activity could also explain the increased SP frequency we observed. This hypothetical mechanism would also be independent of microenvirinment. In summary, we surmise that HSCs have a mechanism that copes with cellular damage while compensating for the reduced cellular output of HSCs with age by increasing the absolute number of HSCs. Figure Figure

Developing a Model of Human Pluripotent to Hematopoietic Stem Cell Development in Mistrg Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4755-4755
Author(s):  
John Astle ◽  
Yangfei Xiang ◽  
Anthony Rongvaux ◽  
Carla Weibel ◽  
Henchey Elizabeth ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice

Abstract De novo generation of HSCs has been described as a "holy grail" of stem cell biology, however the factors required for converting human pluripotent stem cells (PSCs) to true hematopoietic stem cells (HSCs) capable of robust long-term engraftment have yet to be fully characterized. Two groups have shown that injection of PSCs into immunodeficient mice leads to teratomas containing niches producing hematopoietic progenitors capable of long-term engraftment. Once these hematopoietic progenitors and their microenvironments are better characterized, this system could be used as a model to help direct in vitro differentiation of PSCs to HSCs. Toward this end, we have injected human PSCs into immunodeficient mice expressing human rather than mouse M-CSF, IL-3, GM-CSF, and thrombopoietin, as well as both human and mouse versions of the "don't eat me signal" Sirpa (collectively termed MISTRG mice). These cytokines are known to support different aspects of hematopoiesis, and thrombopoietin in particular has been shown to support HSC maintenance, suggesting these mice may provide a better environment for human PSC-derived HSCs than the more traditional mice used for human HSC engraftment. The majority of teratomas developed so far in MISTRG contain human hematopoietic cells, and the CD34+ population isolated from over half of the teratomas contained hematopoietic colony forming cells by colony forming assay. These findings further corroborate this approach as a viable method for studying human PSC to HSC differentiation. Disclosures No relevant conflicts of interest to declare.

Lysophospholipids synergistically promote primitive hematopoietic cell chemotaxis via a mechanism involving Vav 1

Blood ◽  
2003 ◽  
Vol 102 (8) ◽  
pp. 2798-2802 ◽  
Author(s):  
Anthony D. Whetton ◽  
Yuning Lu ◽  
Andrew Pierce ◽  
Louise Carney ◽  
Elaine Spooncer
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Biology ◽  
Critical Role ◽  
Hematopoietic Cell ◽  
Cell Trafficking ◽  
Hematopoietic Stem ◽  
Stem Cell Trafficking ◽  
Cell Chemotaxis

Abstract Hematopoiesis is sustained by the proliferation and development of an extremely low number of hematopoietic stem cells resident in the bone marrow. These stem cells can migrate from their bone marrow microenvironment and can be found at low levels in the peripheral blood. The factors that regulate egress or ingress of the stem cells from the marrow include cytokines and chemokines. This process of stem cell trafficking is fundamental to both stem cell biology and stem cell transplantation. We show that primitive hematopoietic cells with cobblestone area–forming cell activity express receptors for and display enhanced motility in response to a new class of stem cell agonists, namely lysophospholipids. These agents synergistically promote chemokinestimulated cell chemotaxis, a process that is crucial in stem cell homing. The response to lysophospholipids is mediated by Rac, Rho, and Cdc42 G proteins and the hematopoietic-specific guanyl nucleotide exchange factor Vav 1. Inhibitor studies also show a critical role for phosphatidylinositol 3 kinase (PI3K). Lipid mediators, therefore, regulate the critical process of primitive hematopoietic cell motility via a PI3K- and Vav-dependent mechanism and may govern stem cell movement in vivo. These results are of relevance to understanding stem cell trafficking during bone marrow transplantation.

scholarly journals Hematopoietic stem cells: to be or Notch to be

Blood ◽  
2012 ◽  
Vol 119 (14) ◽  
pp. 3226-3235 ◽  
Author(s):  
Anna Bigas ◽  
Lluis Espinosa
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Development ◽  
Cell Fate ◽  
Cell Biology ◽  
Adult Life ◽  
Notch Pathway ◽  
Hematopoietic Stem ◽  
Experimental Systems ◽  
Cell Diversity

Abstract Notch is a well-conserved signaling pathway and its function in cell fate determination is crucial in embryonic development and in the maintenance of tissue homeostasis during adult life. Notch activation depends on cell-cell interactions that are essential for the generation of cell diversity from initially equivalent cell populations. In the adult hematopoiesis, Notch is undoubtedly a very efficient promoter of T-cell differentiation, and this has masked for a long time the effects of Notch on other blood lineages, which are gradually being identified. However, the adult hematopoietic stem cell (HSC) remains mostly refractory to Notch intervention in experimental systems. In contrast, Notch is essential for the generation of the HSCs, which takes place during embryonic development. This review summarizes the knowledge accumulated in recent years regarding the role of the Notch pathway in the different stages of HSC ontology from embryonic life to fetal and adult bone marrow stem cells. In addition, we briefly examine other systems where Notch regulates specific stem cell capacities, in an attempt to understand how Notch functions in stem cell biology.

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