Investigating The Role Of ARAP3 In The Regulation Of Hematopoietic Stem and Progenitor Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2409-2409
Author(s):  
Yiwen Song ◽  
Sonja Vermeren ◽  
Wei Tong
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Progenitor Cells ◽  
Hematopoietic Cells ◽  
Conditional Knockout ◽  
Ph Domain ◽  
Hematopoietic Stem ◽  
Normal Peripheral Blood ◽  
Stem And Progenitor Cells

Abstract ARAP3 is a member of the dual Arf-and-Rho GTPase-activating proteins (GAP) family, functioning specifically to inactivate its substrates Arf6 and RhoA GTPases. ARAP3 is translocated to the plasma membrane after PIP3 binding to the first two of its five PH domains, facilitating its GAP activity in a PI3K-mediated manner. Rho family GTPases are found to play critical roles in many aspects of hematopoietic stem and progenitor cells (HSPCs), such as engraftment and migration, while a role for Arf family GTPases in hematopoiesis is less defined. Previous studies found that either exogenous ARAP3 expression in epithelial cells or RNAi-mediated ARAP3 depletion in endothelial cells disrupts F-actin or lamellipodia formation, respectively, resulting in a cell rounding phenotype and failure to spread. This implies that ARAP3 control of Arf6 and RhoA is tightly regulated, and maintaining precise regulation of ARAP3 levels is crucial to actin organization in the cell. Although ARAP3 was first identified in porcine leukocytes, its function in the hematopoietic system is incompletely understood. Germline deletion of Arap3 results in embryonic lethality due to angiogenic defects. Since endothelial cells are important for the emergence of HSCs during embryonic development, early lethality precludes further studying the role of ARAP3 in definitive hematopoiesis. Therefore, we generated several transgenic mouse models to manipulate ARAP3 in the hematopoietic compartment: (1) Arap3fl/fl;Vav-Cretg conditional knockout mice (CKO) deletes ARAP3 specifically in hematopoietic cells, (2) Arap3fl/fl;VE-Cadherin -Cretg CKO mice selectively deletes ARAP3 in embryonic endothelial cells and thereby hematopoietic cells, and (3) Arap3R302,3A/R302,3A germline knock-in mice (KI/KI) mutates the first PH domain to ablate PI3K-mediated ARAP3 activity in all tissues. We found an almost 100% and 90% excision efficiency in the Vav-Cretg- and VEC-Cretg- mediated deletion of ARAP3 in the bone marrow (BM), respectively. However, the CKO mice appear normal in steady-state hematopoiesis, showing normal peripheral blood (PB) counts and normal distributions of all lineages in the BM. Interestingly, we observed an expansion of the Lin-Scal+cKit+ (LSK) stem and progenitor compartment in the CKO mice. This is due to an increase in the multi-potent progenitor (MPP) fraction, but not the long-term or short-term HSC (LT- or ST-HSC) fractions. Although loss of ARAP3 does not alter the frequency of phenotypically-characterized HSCs, we performed competitive BM transplantation (BMT) studies to investigate the functional impact of ARAP3 deficiency. 500 LSK cells from Arap3 CKO (Arap3fl/fl;Vav-Cretg and Arap3fl/fl;VEC-Cretg) or Arap3fl/fl control littermate donors were transplanted with competitor BM cells into irradiated recipients. We observed similar donor-derived reconstitution and lineage repopulation in the mice transplanted with Arap3fl/fl and Arap3 CKO HSCs. Moreover, Arap3 CKO HSCs show normal reconstitution in secondary transplants. Arap3 KI/KI mice are also grossly normal and exhibit an expanded MPP compartment. Importantly, Arap3KI/KI LSKs show impaired reconstitution compared to controls in the competitive BMT assays. Upon secondary and tertiary transplantation, reconstitution in both PB and BM diminished in the Arap3KI/KI groups, in contrast to sustained reconstitution in the control group. Additionally, we observed a marked skewing towards the myeloid lineage in Arap3KI/KI transplanted secondary and tertiary recipients. These data suggest a defect in HSC function in Arap3KI/KI mice. Myeloid-skewed reconstitution also points to the possibility of selection for “myeloid-primed” HSCs and against “balanced” HSCs, as HSCs exhaust during aging or upon serial transplantation. Taken together, our data suggest that ARAP3 plays a non-cell-autonomous role in HSCs by regulating HSC niche cells. Alternatively, the ARAP3 PH domain mutant that is incapable of locating to the plasma membrane in response to PI3K may exert a novel dominant negative function in HSCs. We are investigating mechanistically how ARAP3 controls HSC engraftment and self-renewal to elucidate the potential cell-autonomous and non-cell-autonomous roles of ARAP3 in HSCs. In summary, our studies identify a previously unappreciated role of ARAP3 as a regulator of hematopoiesis and hematopoietic stem and progenitor cell function. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Developmental Stage and Sex-Specific Role of IGF/IGF1R Signaling in Hematopoietic Stem and Progenitor Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1157-1157
Author(s):  
Ying Xie ◽  
Xin Hu ◽  
Zhe Li
Keyword(s):  
Developmental Stage ◽  
Progenitor Cells ◽  
Hematopoietic Cells ◽  
Conditional Knockout ◽  
Specific Role ◽  
Hematopoietic Stem ◽  
Male And Female ◽  
Stem And Progenitor Cells ◽  
Igf1r Signaling

Abstract Insulin-like growth factors (IGFs) are critical regulators of cell growth, proliferation and survival. Their activities are mainly mediated through insulin-like growth factor 1 receptor (IGF1R). Both IGFs and IGF1R are commonly involved in human cancers, including leukemia. Thus, a better understanding of the role of IGF/IGF1R signaling in normal hematopoiesis will enhance our understanding of leukemogenesis. We showed previously a developmental stage-specific role of this pathway in regulating fetal (but not adult) megakaryocytic progenitors via interplay with GATA1 (Genes Dev. 24:1659-72). To determine whether IGF/IGF1R signaling also plays differential roles in fetal and adult hematopoiesis in general, we analysed Igf1r conditional knockout mice using Mx1-Cre and Vav-Cre for the adult stage, and Tie2-Cre for the fetal stage. Although both fetal and adult stages of hematopoiesis were not significantly perturbed, loss of Igf1r in fetal (but not in adult) hematopoietic cells led to a significant reduction in the number of CFUs in clonogenic assays. In adult Igf1r -null Lin-Sca-1+c-Kit+ (LSK) hematopoietic stem and progenitor cells (HSPCs), analysis of the long-term hematopoietic stem cell (LT-HSC), short-term HSC (ST-HSC) and multipotent progenitor (MPP) subsets of LSK cells revealed an increase in the percentage of LT-HSCs when compared to that of wild-type (WT) mice, consistent with a recent study (Nature. 500:345-9). These data suggest that IGF/IGF1R signaling may have a developmental stage-restricted role in fetal progenitors; in adults, this pathway may play a role in the transition from LT-HSCs to MPPs. Recently it was shown that estrogen signaling plays an important role in regulating proliferation of HSCs (Nature. 505:555-8). Since during development, both male and female fetuses are exposed to the same high level of maternal estrogen, whereas in adults, male and female hematopoietic cells are exposed to different levels of circulating estrogen, we hypothesized that adult (but not fetal) HSPCs from male and female mice might exhibit different phenotypes in response to Igf1r -loss. To test this, we analysed the adult LSK population by separating males and females. Interestingly, we found that in females, but not in males, the LSK population is significantly reduced upon Igf1r -loss. Conversely, a preliminary study in fetal liver CFU assay revealed that both Igf1r -null female and male fetuses exhibited a similar reduction in their CFUs compared to matched WT controls. To understand the female-specific role of IGF/IGF1R signaling in adult HSPCs, we analysed the cell cycle status of HSCs. Similar to the reported observation (Nature. 505:555-8), we found that in WT female adults, there were significantly more Ki67+ cycling LT-HSCs than those in males. Intriguingly, Igf1r -loss significantly reduced the percentage of cycling LT-HSCs in females to a level comparable to that of WT males, but had a neglectable effect on cycling LT-HSCs in males. Administration of estradiol (E2) revealed that in females, E2 injection led to an increase in the percentage of Ki67+ LT-HSCs and this increase was partially abolished when under the Igf1r- null background; in males, E2 injection also increased the percentage of Ki67+ LT-HSCs, although we did not observe a notable reduction in this population when under the Igf1r -null background. Overall, our data suggest that although IGF/IGF1R signaling is not essential for normal hematopoiesis, it may play a more important role under conditions (e.g., fetal development, pregnancy) when there is a higher demand for the output from the hematopoietic system; in particular, this pathway may play an important role in mediating the effect of estrogen on self-renewal and proliferation of HSPCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Endothelial Cells Promote Expansion of Long-Term Engrafting Marrow Hematopoietic Stem and Progenitor Cells in Primates

2016 ◽  
Vol 6 (3) ◽  
pp. 864-876 ◽  
Author(s):  
Jennifer L. Gori ◽  
Jason M. Butler ◽  
Balvir Kunar ◽  
Michael G. Poulos ◽  
Michael Ginsberg ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Progenitor Cells ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

scholarly journals The N-glycome regulates the endothelial-to-hematopoietic transition

Science ◽  
2020 ◽  
Vol 370 (6521) ◽  
pp. 1186-1191
Author(s):  
Dionna M. Kasper ◽  
Jared Hintzen ◽  
Yinyu Wu ◽  
Joey J. Ghersi ◽  
Hanna K. Mandl ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Progenitor Cells ◽  
Specific Expression ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
High Mannose

Definitive hematopoietic stem and progenitor cells (HSPCs) arise from the transdifferentiation of hemogenic endothelial cells (hemECs). The mechanisms of this endothelial-to-hematopoietic transition (EHT) are poorly understood. We show that microRNA-223 (miR-223)–mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT. miR-223 is enriched in hemECs and in oligopotent nascent HSPCs. miR-223 restricts the EHT of lymphoid-myeloid lineages by suppressing the mannosyltransferase alg2 and sialyltransferase st3gal2, two enzymes involved in protein N-glycosylation. ECs that lack miR-223 showed a decrease of high mannose versus sialylated sugars on N-glycoproteins such as the metalloprotease Adam10. EC-specific expression of an N-glycan Adam10 mutant or of the N-glycoenzymes phenocopied miR-223 mutant defects. Thus, the N-glycome is an intrinsic regulator of EHT, serving as a key determinant of the hematopoietic fate.

Role of HMGA2 in human hematopoietic stem and progenitor cells

2013 ◽  
Vol 41 (8) ◽  
pp. S44
Author(s):  
Praveen Kumar ◽  
Aurélie Baudet ◽  
Ineke De Jong ◽  
Jonas Larsson
Keyword(s):  
Progenitor Cells ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Mesenchymal Stem and Progenitor Cells In the Mouse Bone Marrow Lack Expression of CD44.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2581-2581
Author(s):  
Hong Qian ◽  
Mikael Sigvardsson
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Hematopoietic Cells ◽  
Hematopoietic Stem ◽  
Colony Forming Unit ◽  
Stem And Progenitor Cells ◽  
Cell Fractions

Abstract Abstract 2581 The bone marrow (BM) microenvironment consists of a heterogeneous population including mesenchymal stem cells and as well as more differentiated cells like osteoblast and adipocytes. These cells are believed to be crucial regulators of hematopoetic cell development, however, so far, their identity and specific functions has not been well defined. We have by using Ebf2 reporter transgenic Tg(Ebf2-Gfp) mice found that CD45−TER119−EBF2+ cells are selectively expressed in non-hematopoietic cells in mouse BM and highly enriched with MSCs whereas the EBF2− stromal cells are very heterogenous (Qian, et al., manuscript, 2010). In the present study, we have subfractionated the EBF2− stromal cells by fluorescent activated cell sorter (FACS) using CD44. On contrary to previous findings on cultured MSCs, we found that the freshly isolated CD45−TER119−EBF2+ MSCs were absent for CD44 whereas around 40% of the CD45−TER119−EBF2− cells express CD44. Colony forming unit-fibroblast (CFU-F) assay revealed that among the CD45−LIN−EBF2− cells, CD44− cells contained generated 20-fold more CFU-Fs (1/140) than the CD44+ cells. The EBF2−CD44− cells could be grown sustainably in vitro while the CD44+ cells could not, suggesting that Cd44− cells represents a more primitive cell population. In agreement with this, global gene expression analysis revealed that the CD44− cells, but not in the CD44+ cells expressed a set of genes including connective tissue growth factor (Ctgf), collagen type I (Col1a1), NOV and Runx2 and Necdin(Ndn) known to mark MSCs (Djouad et al., 2007) (Tanabe et al., 2008). Furthermore, microarray data and Q-PCR analysis from two independent experiments revealed a dramatic downregulation of cell cycle genes including Cdc6, Cdca7,-8 and Ki67, Cdk4-6) and up-regulation of Cdkis such as p57 and p21 in the EBF2−CD44− cells, compared to the CD44+ cells indicating a relatively quiescent state of the CD44− cells ex vivo. This was confirmed by FACS analysis of KI67 staining. Furthermore, our microarray analysis suggested high expression of a set of hematopoietic growth factors and cytokines genes including Angiopoietin like 1, Kit ligand, Cxcl12 and Jag-1 in the EBF2−CD44− stromal cells in comparison with that in the EBF2+ or EBF2−CD44+ cell fractions, indicating a potential role of the EBF2− cells in hematopoiesis. The hematopoiesis supporting activity of the different stromal cell fractions were tested by in vitro hematopoietic stem and progenitor assays- cobblestone area forming cells (CAFC) and colony forming unit in culture (CFU-C). We found an increased numbers of CAFCs and CFU-Cs from hematopoietic stem and progenitor cells (Lineage−SCA1+KIT+) in culture with feeder layer of the EBF2−CD44− cells, compared to that in culture with previously defined EBF2+ MSCs (Qian, et al., manuscript, 2010), confirming a high capacity of the EBF2−CD44− cells to support hematopoietic stem and progenitor cell activities. Since the EBF2+ cells display a much higher CFU-F cloning frequency (1/6) than the CD44−EBF2− cells, this would also indicate that MSCs might not be the most critical regulators of HSC activity. Taken together, we have identified three functionally and molecularly distinct cell populations by using CD44 and transgenic EBF2 expression and provided clear evidence of that primary mesenchymal stem and progenitor cells reside in the CD44− cell fraction in mouse BM. The findings provide new evidence for biological and molecular features of primary stromal cell subsets and important basis for future identification of stage-specific cellular and molecular interaction pathways between hematopoietic cells and their cellular niche components. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Deletion of proapoptotic Puma selectively protects hematopoietic stem and progenitor cells against high-dose radiation

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4707-4714 ◽  
Author(s):  
Lijian Shao ◽  
Yan Sun ◽  
Zhonghui Zhang ◽  
Wei Feng ◽  
Yongxing Gao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Hematopoietic Cells ◽  
High Dose ◽  
Adverse Side Effect ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Novel Strategy ◽  
Induced Apoptosis ◽  
Dose Radiation

Abstract Bone marrow injury is a major adverse side effect of radiation and chemotherapy. Attempts to limit such damage are warranted, but their success requires a better understanding of how radiation and anticancer drugs harm the bone marrow. Here, we report one pivotal role of the BH3-only protein Puma in the radiosensitivity of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Puma deficiency in mice confers resistance to high-dose radiation in a hematopoietic cell–autonomous manner. Unexpectedly, loss of one Puma allele is sufficient to confer mice radioresistance. Interestingly, null mutation in Puma protects both primitive and differentiated hematopoietic cells from damage caused by low-dose radiation but selectively protects HSCs and HPCs against high-dose radiation, thereby accelerating hematopoietic regeneration. Consistent with these findings, Puma is required for radiation-induced apoptosis in HSCs and HPCs, and Puma is selectively induced by irradiation in primitive hematopoietic cells, and this induction is impaired in Puma-heterozygous cells. Together, our data indicate that selective targeting of p53 downstream apoptotic targets may represent a novel strategy to protecting HSCs and HPCs in patients undergoing intensive cancer radiotherapy and chemotherapy.

scholarly journals p53-dependent induction of P2X7 on hematopoietic stem and progenitor cells regulates hematopoietic response to genotoxic stress

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Lin Tze Tung ◽  
HanChen Wang ◽  
Jad I. Belle ◽  
Jessica C. Petrov ◽  
David Langlais ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Whole Body ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Stem And Progenitor Cells ◽  
Hematopoietic Response

AbstractStem and progenitor cells are the main mediators of tissue renewal and repair, both under homeostatic conditions and in response to physiological stress and injury. Hematopoietic system is responsible for the regeneration of blood and immune cells and is maintained by bone marrow-resident hematopoietic stem and progenitor cells (HSPCs). Hematopoietic system is particularly susceptible to injury in response to genotoxic stress, resulting in the risk of bone marrow failure and secondary malignancies in cancer patients undergoing radiotherapy. Here we analyze the in vivo transcriptional response of HSPCs to genotoxic stress in a mouse whole-body irradiation model and, together with p53 ChIP-Seq and studies in p53-knockout (p53KO) mice, characterize the p53-dependent and p53-independent branches of this transcriptional response. Our work demonstrates the p53-independent induction of inflammatory transcriptional signatures in HSPCs in response to genotoxic stress and identifies multiple novel p53-target genes induced in HSPCs in response to whole-body irradiation. In particular, we establish the direct p53-mediated induction of P2X7 expression on HSCs and HSPCs in response to genotoxic stress. We further demonstrate the role of P2X7 in hematopoietic response to acute genotoxic stress, with P2X7 deficiency significantly extending mouse survival in irradiation-induced hematopoietic failure. We also demonstrate the role of P2X7 in the context of long-term HSC regenerative fitness following sublethal irradiation. Overall our studies provide important insights into the mechanisms of HSC response to genotoxic stress and further suggest P2X7 as a target for pharmacological modulation of HSC fitness and hematopoietic response to genotoxic injury.

scholarly journals TNFα Rescues Dendritic Cell Development in Hematopoietic Stem and Progenitor Cells Lacking C/EBPα

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1223
Author(s):  
Subramanian Anirudh ◽  
Angelika Rosenberger ◽  
Elke Schwarzenberger ◽  
Carolin Schaefer ◽  
Herbert Strobl ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Gene Expression Analysis ◽  
Hematopoietic Stem ◽  
Reporter Mouse ◽  
Multistep Process ◽  
Stem And Progenitor Cells ◽  
Culture Supernatants ◽  
Cytokine Profiling

Dendritic cells (DCs) are crucial effectors of the immune system, which are formed from hematopoietic stem and progenitor cells (HSPCs) by a multistep process regulated by cytokines and distinct transcriptional mechanisms. C/EBPα is an important myeloid transcription factor, but its role in DC formation is not well defined. Using a CebpaCre-EYFP reporter mouse model, we show that the majority of splenic conventional DCs are derived from Cebpa-expressing HSPCs. Furthermore, HSPCs isolated from Cebpa knockout (KO) mice exhibited a marked reduced ability to form mature DCs after in vitro culture with FLT3L. Differentiation analysis revealed that C/EBPα was needed for the formation of monocytic dendritic progenitors and their transition to common dendritic progenitors. Gene expression analysis and cytokine profiling of culture supernatants showed significant downregulation of inflammatory cytokines, including TNFα and IL-1β as well as distinct chemokines in KO HSPCs. In addition, TNFα-induced genes were among the most dysregulated genes in KO HSPCs. Intriguingly, supplementation of in vitro cultures with TNFα at least partially rescued DC formation of KO HSPCs, resulting in fully functional, mature DCs. In conclusion, these results reveal an important role of C/EBPα in early DC development, which in part can be substituted by the inflammatory cytokine TNFα.

Blood Flow Is Required for the Release of Hematopoietic Stem- and Progenitor Cells From Hemogenic Endothelium in the Placenta.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 698-698
Author(s):  
Katrin E Rhodes ◽  
Ben Van Handel ◽  
Michele Wang ◽  
Yanling Wang ◽  
Akanksha Chhabra ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Yolk Sac ◽  
Positive Staining ◽  
Hemogenic Endothelium ◽  
Hematopoietic Stem ◽  
Notch1 Signaling ◽  
Stem And Progenitor Cells

Abstract Abstract 698 Hematopoietic stem cells (HSCs) are required for continuous blood cell production throughout life. HSCs emerge only within a short developmental time window during embryogenesis. Mounting evidence posits that HSCs arise directly from hemogenic endothelial cells during midgestation within the large arteries of the conceptus, which include the dorsal aorta, the umbilical and vitelline arteries and the chorioallantoic vessels of the placenta. However, the microenvironmental signals that mediate this temporally regulated process remain unclear. Here we examine, by using Ncx1−/− embryos that lack heartbeat and circulation, how blood flow imparts instructive cues that ensure proper HSC development. Immunostaining revealed that CD41+ hematopoietic cells, although present, were markedly decreased in Ncx1-/-placentas as compared to wild-type controls. Furthermore, mutant placentas evidenced large clusters of round CD31+ cells protruding into the lumens of the chorioallantoic vessels. Based on these data, we hypothesized that lack of blood flow may impede the generation of hematopoietic stem and progenitor cells (HS/PCs) and that the endothelial clusters represent hemogenic intermediates. FACS analysis and colony forming assays confirmed a dramatic reduction in the number of clonogenic progenitors in the placenta and the embryo proper of Ncx mutants, while the yolk sac was unaffected. However, HS/PC generation in the placenta and embryo could be rescued by culturing explants on OP9 stroma before plating in colony forming assays, verifying intact hematopoietic potential. To determine if the rescue observed was due to expansion of existing progenitors or generation of new HS/PCs, we sorted CD41medckit+hematopoietic progenitors and CD31+CD41− endothelial cells from hematopoietic tissues and co-cultured them on stroma. These experiments demonstrated that endothelial cells from placenta, embryo proper and yolk sac can generate HS/PCs following stroma stimulation, confirming the presence of hemogenic endothelium in these organs. Immunostaining of Ncx−/− placentas revealed that although the development of the arterio-venous vascular network was impaired, Notch1 signaling, required for both arterial specification and HSC development, was robust in cells of the endothelial clusters. Furthermore, positive staining for Runx1 and c-myb indicated that cells in the clusters had activated the hematopoietic program. Interestingly, electron microscopy demonstrated that cells in the clusters were tethered to each other via adherens junctions, a characteristic of endothelial cells. In addition, they also maintained high levels of Flk1, expressed VEGF and were actively proliferating, consistent with exposure to extended hypoxia. These data suggest that although cells in the clusters have initiated hematopoietic commitment, they are unable to down-regulate their endothelial identity and complete hematopoietic emergence, resulting in the formation of clusters of hemogenic intermediates. These results imply that cues imparted via circulation are required to complete the commitment to a hematopoietic fate from hemogenic endothelium. Data from co-culture experiments suggest that prolonged Notch1 signaling impairs hematopoietic emergence from hemogenic endothelial cells, and may account for the HSC emergence defect in the absence of blood flow. Overall, these data suggest that blood flow and circulating primitive red blood cells are critical components of the dynamic microenvironment necessary to both relieve the hypoxia required for the specification and proliferation of hemogenic endothelium and provide important mechanical and/or molecular signals required by HSCs to fully commit to the hematopoietic fate and complete emergence. Disclosures: No relevant conflicts of interest to declare.

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