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Transcriptome analysis of ITGA3+ and ITGA3- from expanded CB cells

ABSTRACT: Cell purification technology combined with whole transcriptome sequencing and small molecule agonist of hematopoietic stem cell self-renewal has allowed us to identify ITGA3 as a surface maker that defines a rare subpopulation of human cells which is highly enriched for stem cell activity in vivo. ITGA3-positive cells (within the EPCR+CD90+CD133+CD34+CD45RA- fraction) exhibit a robust multi-lineage differentiation potential and serial reconstitution in immunocompromised mice. In culture, most if not all of the HSC activity is detected in the ITGA3+ subset, arguing for the stability of this marker on the surface of cultured cells, a feature not found with more recently described markers such as CD49f. Functionally ITGA3 is essential for human HSC activity in vivo. Its exploitation should open new possibilities in our effort to understand the molecular bases behind HSC self-renewal.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130974 | GEO | 2020/04/20

REPOSITORIES: GEO

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EPCR Expression Defines the Most Primitive Subset of Human HSPC and Is Required for Their In Vivo Activity

Project description:Cell purification technology combined with whole transcriptome sequencing and small molecule agonist of hematopoietic stem cell self-renewal has allowed us to identify the endothelial protein c receptor protein (EPCR) as a surface maker that defines a rare subpopulation of human cells which is highly enriched for stem cell activity in vivo. EPCR-positive cells exhibit a robust multi-lineage differentiation potential and serial reconstitution in immunocompromised mice. In culture, most if not all of the HSC activity is detected in the EPCR+ subset, arguing for the stability of this marker on the surface of cultured cells, a feature not found with more recently described markers such as CD49f. Functionally EPCR is essential for human HSC activity in vivo. Cells engineered to express low EPCR expression proliferate normally in culture but lack the ability to confer long-term reconstitution. EPCR is thus a stable marker for human HSC. Its exploitation should open new possibilities in our effort to understand the molecular bases behind HSC self-renewal.

2017-06-22 | GSE77128 | GEO

Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment

Project description:Gene expression profiling was used to investigate the relationship between human cord blood hematopoietic stem cells (HSC) and multipotent progenitors described in the study. Genes more highly expressed in HSC may be associated with stem cell function and self-renewal. Total RNA was obtained from flow-sorted populations based on the cell surface expression of CD34, CD38, CD45RA, Thy1, and CD49f.

2011-07-31 | E-GEOD-29105 | biostudies-arrayexpress

UM171 induces a homeostatic inflammatory-detoxification response supporting human HSC self-renewal

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2019-11-25 | GSE138680 | GEO

Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation and Self-Renewal

Project description:Hematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential is variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings suggest a new molecular basis for HSC control and expansion. Adult mouse bone marrow CD45+EPCR+CD48-CD150+ cells were used in a total of 4 conditions (fresh, 6 hour stimulation with SF+IL-11+UG26 CM, UG26 CM only, SF+IL-11) with 2 technical replicates per condition.

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Single Cell analysis of the most primitive Human Hematopoietic Stem Cell Population.

Project description:Single cell transcriptomic profiling (sc RNA-seq) of the most primitive Human Hematopoietic Stem Cell Population described: CD34+CD38-CD45RA-CD49f+EPCR+ (hereafter EPCR+).

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miR-125a Confers Multi-Lineage Long-Term Repopulating Stem Cell Activity to Murine and Human Hematopoietic Progenitors

Project description:Umbilical cord blood (CB) is a non-invasive, convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. One feasible option would be to expand HSCs to improve therapeutic outcome, however available protocols and the molecular mechanisms governing the self-renewal of HSC are unclear. Here we show that ectopic expression of a single miRNA, miR-125a, in purified murine and human multipotent progenitors (MPP) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and Western blot analysis, we identified a restricted set of miR-125a targets which revealed the involvement of the MAP kinase signaling pathway in conferring long-term repopulating capacity to multipotent progenitors in human and mice. Our findings offer the innovative potential to use MPP with enhanced self-renewal activity to augment limited sources of HSC to improve clinical protocols.

2017-01-11 | PXD003931 | Pride

Expression data of human fetal liver hematopoietic stem and progenitors cells [Set 2]

Project description:Advances in pluripotent stem cell and reprogramming technologies have given hope of generating hematopoietic stem cells (HSC) in culture. To succeed, greater understanding of the self-renewing HSC during human development is required. We discovered that glycophosphatidylinositol-anchored surface protein GPI-80 (Vanin 2) defines a distinct subpopulation of human fetal hematopoietic stem/progenitor cells (HSPC) with self-renewal ability. CD34+CD90+CD38-GPI-80+ HSPC were the sole population that maintained proliferative potential and undifferentiated state in bone marrow stroma co-culture, and engrafted in immunodeficient mice. GPI-80 expression also enabled tracking of HSC migration between human fetal hematopoietic niches. The most highly enriched surface protein in GPI-80+ HSPC as compared to their progeny was Integrin alpha-M (ITGAM), which in leukocytes cooperates with GPI-80 to support migration. Knockdown of either GPI-80 or ITGAM was sufficient to perturb undifferentiated HSPC in stroma co-culture. These findings indicate that human fetal HSC utilize common mechanisms with leukocytes for cell-cell interactions governing HSC self-renewal. We used microarrays to identify genes enriched in the GPI-80+ hematopoietic stem and progenitor population in fetal liver. RNA was extracted from enriched fetal liver hematopoietic stem and progenitor cells, and downstream progenitors, for comparison based on Affymetrix arrays.

2015-01-23 | E-GEOD-54315 | biostudies-arrayexpress

Expression data of human fetal liver hematopoietic stem and progenitors cells [Set 1]

Project description:Advances in pluripotent stem cell and reprogramming technologies have given hope of generating hematopoietic stem cells (HSC) in culture. To succeed, greater understanding of the self-renewing HSC during human development is required. We discovered that glycophosphatidylinositol-anchored surface protein GPI-80 (Vanin 2) defines a distinct subpopulation of human fetal hematopoietic stem/progenitor cells (HSPC) with self-renewal ability. CD34+CD90+CD38-GPI-80+ HSPC were the sole population that maintained proliferative potential and undifferentiated state in bone marrow stroma co-culture, and engrafted in immunodeficient mice. GPI-80 expression also enabled tracking of HSC migration between human fetal hematopoietic niches. The most highly enriched surface protein in GPI-80+ HSPC as compared to their progeny was Integrin alpha-M (ITGAM), which in leukocytes cooperates with GPI-80 to support migration. Knockdown of either GPI-80 or ITGAM was sufficient to perturb undifferentiated HSPC in stroma co-culture. These findings indicate that human fetal HSC utilize common mechanisms with leukocytes for cell-cell interactions governing HSC self-renewal. We used microarrays to identify genes enriched in the CD90+ hematopoietic stem and progenitor population in fetal liver. RNA was extracted from enriched fetal liver hematopoietic stem and progenitor cells, and downstream progenitors, for comparison based on Affymetrix arrays.

2015-01-23 | E-GEOD-54314 | biostudies-arrayexpress

Loss of Phf6 enhances HSC self-renewal and leukemia stem cell activity

Project description:Loss of Phf6 enhances HSC self-renewal and leukemia stem cell activity

| PRJNA740257 | ENA

Oncogenic Nras has a bimodal effect on hematopoietic stem cells promoting proliferation and self-renewal

Project description:Pre-leukemic mutations are thought to promote clonal expansion of hematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness. However, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative disease and leukemia. Here we show that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all without immortalizing HSCs or causing leukemia in our experiments. NrasG12D also confers long-term self-renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal we assessed HSC cell cycle kinetics using H2B-GFP label retention. We found that NrasG12D had a bimodal effect on HSCs, increasing the proliferation of some HSCs while increasing the quiescence and competitiveness of other HSCs. One signal can therefore increase HSC proliferation, competitiveness, and self-renewal through a bimodal effect that promotes proliferation in some HSCs and quiescence in others. 12 RNA samples from mouse bone marrows were analyzed. There are three biological replicates for each subtype.

2014-03-14 | E-GEOD-45194 | biostudies-arrayexpress

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