scholarly journals Wnt/β-Catenin Signaling Cooperates With PTEN/PI3K/Akt Signaling In Vivo and Ex Vivo To Promote Hematopoietic Stem Cell Self-Renewal and Expansion

2011 ◽  
Vol 17 (2) ◽  
pp. S271
Author(s):  
J.M. Perry ◽  
X.C. He ◽  
J.C. Grindley ◽  
S. Abhyankar ◽  
C. Weiner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Ex Vivo ◽  
Akt Signaling ◽  
Self Renewal ◽  
Hematopoietic Stem

scholarly journals Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential

Blood ◽  
2009 ◽  
Vol 114 (17) ◽  
pp. 3557-3566 ◽  
Author(s):  
Haiming Xu ◽  
Satyam Eleswarapu ◽  
Hartmut Geiger ◽  
Kathleen Szczur ◽  
Deidre Daria ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Rho Gtpase ◽  
Ex Vivo ◽  
Negative Regulator ◽  
Transcriptional Analysis ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Hematopoietic stem cell (HSC) engraftment is a multistep process involving HSC homing to bone marrow, self-renewal, proliferation, and differentiation to mature blood cells. Here, we show that loss of p190-B RhoGTPase activating protein, a negative regulator of Rho GTPases, results in enhanced long-term engraftment during serial transplantation. This effect is associated with maintenance of functional HSC-enriched cells. Furthermore, loss of p190-B led to marked improvement of HSC in vivo repopulation capacity during ex vivo culture without altering proliferation and multilineage differentiation of HSC and progeny. Transcriptional analysis revealed that p190-B deficiency represses the up-regulation of p16Ink4a in HSCs in primary and secondary transplantation recipients, providing a possible mechanism of p190-B–mediated HSC functions. Our study defines p190-B as a critical transducer element of HSC self-renewal activity and long-term engraftment, thus suggesting that p190-B is a target for HSC-based therapies requiring maintenance of engraftment phenotype.

scholarly journals Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo

2019 ◽  
Vol 116 (4) ◽  
pp. 1447-1456 ◽  
Author(s):  
Rong Lu ◽  
Agnieszka Czechowicz ◽  
Jun Seita ◽  
Du Jiang ◽  
Irving L. Weissman
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Lineage Commitment ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Different Levels

While the aggregate differentiation of the hematopoietic stem cell (HSC) population has been extensively studied, little is known about the lineage commitment process of individual HSC clones. Here, we provide lineage commitment maps of HSC clones under homeostasis and after perturbations of the endogenous hematopoietic system. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the hematopoietic system has been perturbed by irradiation or by an antagonistic anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiate. Some of these clones dominantly expand and exhibit lineage bias. We identified the cellular origins of clonal dominance and lineage bias and uncovered the lineage commitment pathways that lead HSC clones to different levels of self-renewal and blood production under various transplantation conditions. This study reveals surprising alterations in HSC fate decisions directed by conditioning and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.

Enhanced Human Hematopoietic Stem Cell Self-Renewal Enabled by Controlling Feedback Signaling From Lineage Committed Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1274-1274
Author(s):  
Elizabeth Csaszar ◽  
Daniel Kirouac ◽  
Mei Yu ◽  
Caryn Ito ◽  
Peter W. Zandstra
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Population ◽  
Ex Vivo ◽  
Stem Cell Population ◽  
Fed Batch ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Numbers

Abstract Abstract 1274 Clinical outcomes of hematopoietic stem cell (HSC) transplantation are correlated with infused progenitor cell dose. Limited cell numbers in a typical umbilical cord blood (UCB) unit restricts the therapeutic potential of UCB and motivates ex vivo expansion of these cells. Strategies to grow HSCs have relied on the supplement of molecules acting directly on the stem cell population; however, in all cases, sustained HSC growth is limited by the concurrent growth of more mature cells and their endogenously produced inhibitory signaling factors. Despite increasing evidence for the important role of intercellular (between cell) communication networks, the identity and impact of non-stem cell autonomous feedback signaling remains poorly understood. Simultaneous kinetic tracking of more than 30 secreted factors produced during UCB culture, including TGF-b1, MIP-1b, and MCP-1, in combination with computational simulations of cell population dynamics, enabled us to develop a global control strategy predicted to reduce inhibitory paracrine signaling and, consequently, increase HSC self-renewal. By maintaining endogenously produced ligands at specified levels using a tuneable fed-batch (automated media dilution) strategy, we achieved significant improvements in expansions of total cell numbers (∼180-fold), CD34+ cells (∼80-fold), and NOD/SCID/IL-2Rgc-null (NSG) repopulating cells (∼11-fold, detected at limiting dilution). The fed-batch strategy has been integrated into an automated bioreactor, allowing for the generation of a clinically-relevant cell product after 12 days of culture, with minimal user manipulation. As this strategy targets the HSC environment and not the stem cells directly, it has the ability to act in combination with other expansion strategies to produce synergistic results. Unexpectedly, supplementation of the soluble protein, TAT-HOXB4, to the system, yielded the expected boost in progenitor expansion only in “sub-optimal” control conditions but not in the fed-batch system. Hypothesizing that the efficacy of HOXB4 may be dependent on the skewing of supportive vs. non-supportive cell populations, and the consequent impact of paracrine ligand production, we performed kinetic tracking of 20 hematopoietic cell types during several supportive (fed-batch, HOXB4 supplemented, Notch ligand Delta1 supplemented) vs. non-supportive (control) cultures. Meta analysis of these data revealed a non-autonomous link between HOXB4, increased megakaryocyte production, and stem cell proliferation, as well as between Notch delta-1 ligand, decreased myeloid cell production, and a decrease in the growth inhibition of stem cells. These predictions have been experimentally validated using co-cultures of sorted purified HSCs and CD41+ megakaryocykes and CD14+ monocytes. Our results identify complex connections between mature cell lineages and stem cell fate decisions and we expect to report a direct link between cell-cell interactions emerging from culture manipulations and the resulting impact on HSC self-renewal. Collectively, these studies support a dominant role for non-stem cell autonomous feedback signaling in the regulation of HSC self-renewal. Overcoming cell non-autonomous inhibition of HSC self-renewal has allowed for novel strategies to enhance HSC numbers ex vivo, thereby facilitating the production of clinically relevant quantities of stem and progenitor cells and enabling more effective strategies to treat hematologic disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Enforcing Post-Transcriptional Circuitries to Achieve Human Hematopoietic Stem Cell Expansion

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-46-SCI-46
Author(s):  
Kristin Hope
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Self Renewal ◽  
Control Of Gene Expression ◽  
Hematopoietic Stem

Abstract The balance between hematopoietic stem cell (HSC) differentiation and self-renewal is central to clinical regenerative paradigms. Unravelling the precise molecular mechanisms that govern HSC fate choices will thus have far reaching consequences for the development of effective therapies for hematopoietic and immunological disorders. There is an emerging recognition that beyond transcription, HSC homeostasis is subject to post-transcriptional control by RNA-binding proteins (RBPs) that ensure precise control of gene expression by modulating mRNA splicing, polyadenylation, localization, degradation or translation. RBPs can synchronously regulate the fates of operationally similar RNAs, in what have been termed RNA regulons. We have used a variety of functional approaches, in combination with unbiased genome- and proteome-scale, methods to define the tenets that govern this regulation and to determine key downstream circuitries of stem cell-regulating RBPs whose targeting could provide the basis for novel regenerative treatments. Through loss-of-function efforts, we have identified the RBP, MSI2, as a required factor for human HSC maintenance. By contrast, at supraphysiological levels, MSI2 has a profound positive effect on human HSC self-renewal decisions. Using a combination of global profiling, including mapping MSI2's targets through cross-linking immunoprecipitation (CLIP)-seq, we show that MSI2 achieves its ex vivo self-renewal-promoting effects by directing a co-ordinated post-transcriptional repression of key targets within the aryl hydrocarbon receptor (AHR) pathway. We are currently exploring the "rules" by which MSI2 influences its downstream effects on target RNAs and how it functions, in combination with other protein interactors, to instill a putative RBP regulatory code in HSCs. HSCs exhibit highly unique epigenomes, transcriptomes and proteomes and it is this distinctive molecular landscape that provides the canvas upon which MSI2, and indeed any other HSC-specific RBP exert their post-transcriptional influence over stem cell function. As such, to decipher the bona fide RNA networks that RBPs function upon in HSCs and to understand how they influence this network to enforce self-renewal, we are working towards performing systematic studies of RBP regulons in these cells specifically. In turn these approaches are elucidating a host of RBPs and post-transcriptional control mechanisms previously unappreciated for their role in HSC control. When modulated appropriately, we can successfully tailor these post-transcriptional regulons to enforce desired HSC outputs ex vivo. In summary, approaches to elucidate key HSC-regulatory RBPs and their protein and RNA interactomes provide valuable insights into a layer of HSC control previously not well understood, and one that can be capitalized on to achieve successful HSC expansion. Disclosures No relevant conflicts of interest to declare.

scholarly journals Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal Via Control of mTOR Signaling

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1160-1160
Author(s):  
Xiao Yan ◽  
Heather A Himburg ◽  
Phuong L Doan ◽  
Mamle Quarmyne ◽  
Evelyn Tran ◽  
...  
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Hematopoietic Stem Cell ◽  
Growth Factor Receptor ◽  
Post Transplantation ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Donor Cells ◽  
Duke University

Abstract Elucidation of the mechanisms governing HSC regeneration has been impeded by difficulty in isolating HSCs early following genotoxic injury, such as total body irradiation (TBI). Using multiparametric flow cytometric cell sorting of BM ckit+sca-1+lin- cells coupled with gene expression analysis, we identified growth factor receptor-bound protein 10 (Grb10), a co-receptor which regulates Insulin Receptor/IGF-1 signaling, to be significantly overexpressed by BM KSL cells at the earliest detectable point of regeneration (day +10) following TBI (3.3-fold, p<0.0001). Grb10 is a member of the imprinted gene family which is predominately expressed in the stem cells of a variety of tissues, including embryonic stem cells, bone marrow, skin and muscle. Viral shRNA-mediated knockdown of Grb10 in BM KSL cells caused a significant decrease in KSL cells and colony forming cells (CFCs) detected in 7-day culture (p=0.03 and p=0.002, respectively). Furthermore, mice competitively transplanted with Grb10-deficient HSCs displayed 10-fold lower donor, multilineage hematopoietic cell engraftment than mice transplanted with Grb10-expressing HSCs (p=0.007 for %CD45.1+ donor cells). Secondary competitive repopulation assays confirmed a greater than 10-fold deficit in long-term repopulating capacity in Grb10-deficient KSL cells compared to Grb10-expressing KSL cells (p=0.006 for %CD45.1+ donor cells). In order to determine if Grb10 was necessary for HSC maintenance and normal hematopoiesis in vivo, we generated maternally-derived Grb10-deficient mice. Heterozygous 8 week old Grb10m/+ (1 mutant allele, 1 wild type allele) had 10-fold decreased Grb10 expression in BM lin-cells. BM CFCs and SLAM+ KSL cells were significantly decreased in Grb10m/+ mice compared to Grb10+/+ mice (p=0.006 and p=0.04, respectively). Competitive repopulation assays demonstrated significantly decreased donor hematopoietic cell repopulation in recipient mice transplanted with Grb10m/+ BM cells versus mice transplanted with Grb10+/+ BM cells (p=0.003 for %CD45.1+ donor cells). Mice transplanted with BM cells from homozygous Grb10-/- mice showed a similar decrease in donor-derived hematopoietic repopulation compared to mice transplanted with BM cells from Grb10+/+ mice (p=0.02 at 20 weeks post-transplantation). These results confirmed that Grb10 regulates HSC self-renewal capacity in vivo. To determine whether Grb10 regulates HSC regeneration after myelotoxic injury, we irradiated Grb10m/+ mice with 550cGy TBI, and monitored hematopoietic recovery over time in comparison to Grb10+/+ controls. Interestingly, Grb10m/+ mice displayed accelerated hematopoietic regeneration early following TBI. At day+10 after 550cGy, Grb10m/+ mice contained significantly increased numbers of BM SLAM+ KSL cells (p=0.04) and CFCs (p=0.009), compared to Grb10+/+ littermates. Similarly, mice transplanted with BM cells from irradiated, Grb10m/+ mice displayed 5-fold increased donor hematopoietic repopulation at 20 weeks post-transplantation compared to mice transplanted with BM cells from irradiated, Grb10+/+ mice (p=0.006). These data suggest that Grb10 deficiency accelerates hematopoietic recovery in the early period following myelosuppressive radiation injury. Mechanistically, Grb10-deficiency caused an increase in the percentage of BM KSL cells in G1 and G2/S/M phase of cell cycle compared to Grb10+/+ KSL cells (p=0.003). We also observed significantly increased levels of mTOR activation in Grb10m/+ BM KSL cells compared to Grb10+/+ BM KSL cells (p=0.001 for pS6, p=0.001 for pS6k and p=0.02 for p4EBP1). Furthermore, mTOR inhibition via siRNA-mTOR targeting rescued the defect in BM hematopoietic progenitor content (colony forming cells) in Grb10-deficient BM cells (p<0.0001). Taken together, our results suggest that Grb10 is necessary for HSC maintenance in steady state, while, paradoxically, Grb10 inhibition accelerates HSC regeneration early following injury. Furthermore, our data suggest that Grb10 mediates these effects via regulation of mTOR signaling. Selective modulation of Grb10 signaling has the potential to augment HSC self-renewal in steady state and to accelerate HSC regeneration following myelotoxic injury. Disclosures Himburg: Duke University: Patents & Royalties: Patent Application for use of Pleiotrophin as a hematopoietic stem cell growth factor. Chute:C2 Regenerate: Equity Ownership; Duke University: Patents & Royalties: Application to use PTN as growth factor as hematopoietic stem cell growth factor.

scholarly journals A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

2021 ◽  
Author(s):  
Richard A. Voit ◽  
Liming Tao ◽  
Fulong Yu ◽  
Liam D. Cato ◽  
Blake Cohen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Regulatory Network ◽  
Genetic Disorder ◽  
Transcriptional Network ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Functional Studies ◽  
Experimental Systems

The molecular regulation of human hematopoietic stem cell (HSC) self-renewal is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC self-renewal. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs exit quiescence. Strikingly, we show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.

Immobilized Thrombopoietin (TPO) Lipopeptide Mimic Supports Similar Signaling and CD34+ Cell Differentiation as Soluble TPO.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3150-3150
Author(s):  
Shara M. Dellatore ◽  
James A. King ◽  
Tor W. Jensen ◽  
Bi-Huang Hu ◽  
Phillip B. Messersmith ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Adhesion ◽  
Ex Vivo ◽  
Lipid Monolayer ◽  
Adherent Cells ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Defined Culture

Abstract Ex vivo expansion of hematopoietic stem cells (HSCs) would greatly facilitate cell and gene therapies. However, HSC division in culture is associated with differentiation. This contrasts with sustained HSC expansion in vivo, and has led to the hypothesis that a stem cell niche supports self-renewal. It is likely that multiple aspects of the niche will have to be mimicked to substantially enhance HSC self-renewal. We are developing a defined culture surface for the presentation of cytokines and cell adhesion molecule (CAM) ligands that are thought to be in the HSC niche. Peptide mimics of CAM ligands and cytokines conjugated to dipalmitoyl glycerol via a polyethylene glycol tether are incorporated into dipalmitoylphosphatidylcholine (DPPC) vesicles and deposited onto a hydrophobic surface to create a lipid monolayer. We have previously shown that this system effectively presents adhesive peptide ligands (Jensen et al., JACS 126:15223, 2004). The strategy for immobilizing lipopeptides has been extended to the presentation of a peptide mimetic for the hematopoietic growth factor thrombopoietin (TPO). The lipopeptide mimetic of TPO is based on the branched dimer mimic (TPOm) developed by Cwirla et al. (Science 276:1696, 1997). We have synthesized two versions of TPOm lipopeptide, the first linked to a lipid at both of the amine termini (TPOm-2L) and the second is linked by a single lipid at the carboxy terminus (TPOm-1L). This immobilization strategy does not interfere with the bioactivity of the TPOm as evidenced by cell adhesion and signaling assays. Adhesion was measured with a normal force assay at 30g using the TPO-responsive M07e cell line. We observed a dose-dependent increase in adhesion, with &lt;5% adherent cells for DPPC surfaces and a plateau of ~70% adherent cells at 1.0 mol% TPOm-1L. There was much less adhesion to TPOm-2L (a maximum of ~25% adhesion). Selective adhesion to the TPOm lipopeptides persisted after 6 days of culture, both in the presence and absence of serum. Culture surfaces with TPOm lipopeptides elicit similar M07e cell signaling response kinetics via the ERK1,2 and STAT5 pathways as compared to soluble TPOm and recombinant human TPO (rhTPO). It is interesting that surface presentation of TPOm synergizes more extensively with stem cell factor (SCF) for the activation of STAT5 than does soluble TPOm. Experiments with bone marrow (BM) CD34+ cells show that surfaces incorporating TPOm-2L supplemented with SCF and flt-3 ligand (FL) support similar overall expansion and protection from apoptosis as controls of soluble TPOm or rhTPO with SCF and FL. Further, there was no difference in the ability of TPOm to retain CD34+ cells or CD34+Thy1+ cells. Also, BM CD34+ cell cultures supplemented with TPOm-1L alone supported similar megakaryocyte maturation, evidenced by the appearance of polyploid CD41+ cells after 9 and 12 days of culture, as those supplemented with soluble TPOm. An advantage of this presentation strategy is the potential to save on cytokines during long-term culture. Feeding cultures stimulated by TPOm lipopeptides requires only exchange of basal media. In summary, we have developed a method to present immobilized TPOm in an active conformation that supports cell adhesion and signaling as well as the expansion and differentiation of CD34+ cells.

Screen for Small Molecules Capable of Expanding Human Hematopoietic Stem Cell Ex Vivo

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1919-1919
Author(s):  
Iman Hatem Fares ◽  
Jalila Chagraoui ◽  
Jana Krosl ◽  
Denis-Claude Roy ◽  
Sandra Cohen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Fold Increase ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Abstract Abstract 1919 Hematopoietic stem cell (HSC) transplantation is a life saving procedure whose applicability is restricted by the lack of suitable donors, by poor responsiveness to mobilization regimens in preparation of autologous transplantations, by insufficient HSC numbers in individual cord blood units, and by the inability to sufficiently amplify HSCs ex vivo. Characterization of Stemregenin (SR1), an aryl hydrocarbon receptor (AHR) antagonist that promotes HSC expansion, provided a proof of principle that low molecular weight (LMW) compounds have the ability to promote HSC expansion. To identify novel putative agonists of HSC self-renewal, we initiated a high throughput screen (HTS) of a library comprising more than 5,000 LMW molecules using the in vitro maintenance of the CD34+CD45RA- phenotype as a model system. Our study was based on the fact that mobilized peripheral blood-derived CD34+CD45RA- cells cultured in media supplemented with: stem cell factor, thrombopoietin, FLT3 ligand and interleukin 6, would promote the expansion of mononuclear cells (MNC) concomitant with a decrease in CD34+CD45RA- population and HSC depletion. LMW compounds preventing this loss could therefore act as agonists of HSC expansion. In a 384-well plate, 2000 CD34+cells were initially cultured/well in 50μl medium comprising 1μM test compounds or 0.1% DMSO (vehicle). The proportions of CD34+CD45RA− cells were determined at the initiation of experiment and after a 7-day incubation. Six of 5,280 LMW compounds (0.11%) promoted CD34+CD45RA− cell expansion, and seventeen (0.32%) enhanced differentiation as determined by the increase in proportions of CD34−CD45RA+ cells compared to control (DMSO). The 6 LMW compounds promoting expansion of the CD34+CD45RA− cell population were re-analyzed in a secondary screen. Four out of these 6 molecules suppressed the transcriptional activity of AHR, suggesting that these compounds share the same molecular pathway as SR1 in stimulating HSC expansion, thus they were not further characterized. The remaining 2 compounds promoted, similar to SR1 or better, a 10-fold and 35-fold expansion of MNC during 7 and 12-day incubations, respectively. The expanded cell populations comprised 65–75% of CD34+ cells compared to 12–30% determined for DMSO controls. During 12-day incubation with these compounds, the numbers of CD34+ cells increased ∼25-fold over their input values, or ∼ 6-fold above the values determined for controls. This expansion of CD34+ cells was associated with a ∼5-fold increase in the numbers of multilineage CFC (granulocyte, erythroid, monocyte, and megakaryocyte, or CFU-GEMM) compared to that found in DMSO control cultures. The ability of the 2 newly identified compounds to expand functional HSCs is currently being evaluated in vivo usingimmunocompromised mice. In conclusion, results of our initial screen suggest that other mechanism, besides inhibition of AhR, are at play for expansion of human HSC. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Wnt Signaling in the Niche Enforces Hematopoietic Stem Cell Quiescence and Is Necessary to Preserve Self-Renewal In Vivo

2008 ◽  
Vol 2 (3) ◽  
pp. 274-283 ◽  
Author(s):  
Heather E. Fleming ◽  
Viktor Janzen ◽  
Cristina Lo Celso ◽  
Jun Guo ◽  
Kathleen M. Leahy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Hematopoietic Stem Cell ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Stem Cell Quiescence ◽  
Cell Quiescence
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