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Mllt3 Governs Self-Renewal And Engraftment Of Human Hematopoietic Stem Cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111484 | GEO | 2019/03/06

REPOSITORIES: GEO

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MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment.

Project description:Limited knowledge of the mechanisms that govern the self-renewal of human haematopoietic stem cells (HSCs), and why this fails in culture, have impeded the expansion of HSCs for transplantation1. Here we identify MLLT3 (also known as AF9) as a crucial regulator of HSCs that is highly enriched in human fetal, neonatal and adult HSCs, but downregulated in culture. Depletion of MLLT3 prevented the maintenance of transplantable human haematopoietic stem or progenitor cells (HSPCs) in culture, whereas stabilizing MLLT3 expression in culture enabled more than 12-fold expansion of transplantable HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Similar to endogenous MLLT3, overexpressed MLLT3 localized to active promoters in HSPCs, sustained levels of H3K79me2 and protected the HSC transcriptional program in culture. MLLT3 thus acts as HSC maintenance factor that links histone reader and modifying activities to modulate HSC gene expression, and may provide a promising approach to expand HSCs for transplantation.

| S-EPMC7278275 | biostudies-literature

Mllt3 Governs Self-Renewal And Engraftment Of Human Hematopoietic Stem Cells

Project description:Mllt3 Governs Self-Renewal And Engraftment Of Human Hematopoietic Stem Cells

| PRJNA437149 | ENA

Alcam regulates long-term hematopoietic stem cell engraftment and self-renewal.

Project description:Hematopoietic stem cells (HSCs) reside in a specialized bone marrow (BM) microenvironment that supports the maintenance and functional integrity of long-term (LT)-HSCs throughout postnatal life. The objective of this work is to study the role of activated leukocyte cell adhesion molecule (Alcam) in HSC differentiation and self-renewal using an Alcam-null (Alcam(-/-) ) mouse model. We show here that Alcam is differentially regulated in adult hematopoiesis and is highly expressed in LT-HSCs where its level progressively increases with age. Young adult Alcam(-/-) mice had normal homeostatic hematopoiesis and normal numbers of phenotypic HSCs. However, Alcam(-/-) HSCs had reduced long-term replating capacity in vitro and reduced long-term engraftment potential upon transplantation. We show that Alcam(-/-) BM contain a markedly lower frequency of long-term repopulating cells than wild type. Further, the long-term repopulating potential and engraftment efficiency of Alcam(-/-) LT-HSCs was greatly compromised despite a progressive increase in phenotypic LT-HSC numbers during long-term serial transplantation. In addition, an age-associated increase in phenotypic LT-HSC cellularity was observed in Alcam(-/-) mice. This increase was predominately within the CD150(hi) fraction and was accompanied by significantly reduced leukocyte output. Consistent with an aging-like phenotype, older Alcam(-/-) LT-HSCs display myeloid-biased repopulation activity upon transplantation. Finally, Alcam(-/-) LT-HSCs display premature elevation of age-associated gene expression, including Selp, Clu, Cdc42, and Foxo3. Together, this study indicates that Alcam regulates functional integrity and self-renewal of LT-HSCs.

| S-EPMC3832064 | biostudies-literature

Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells.

Project description:The generation of all blood cells depends on the ability of hematopoietic stem cells (HSCs) for self-renewal and multilineage differentiation. We show here that the transcription factor Gfi1 is expressed in HSCs and in more mature cells such as common lymphoid progenitors (CLPs) and granulo/monocytic progenitors, but is absent in common myeloid progenitors and megakaryocyte/erythroid progenitors. When Gfi1 is deleted in mice, HSC frequencies are significantly reduced and CLPs all but disappear from the bone marrow. This specific requirement of Gfi1 for the maintenance of HSC numbers is cell autonomous. Transplantation of Gfi1-deficient bone marrow results in a compromised radioprotection and lower numbers of colony forming units in the spleen of wild-type recipients. Strikingly, Gfi1-/- bone marrow cells are severely impaired in competitive long-term reconstituting abilities after transplantation and show a surprisingly high proportion of actively cycling HSCs, suggesting that Gfi1 restrains proliferation of HSCs and thereby regulates their self-renewal and long-term engraftment abilities.

| S-EPMC524350 | biostudies-literature

miR-99 regulates normal and malignant hematopoietic stem cell self-renewal

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-07-27 | GSE101958 | GEO

Alternative Splicing of MBD2 Supports Self-Renewal in Human Pluripotent Stem Cells

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-04-19 | E-GEOD-55679 | biostudies-arrayexpress

The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2011-12-15 | GSE25274 | GEO

KDM5B focuses H3K4 methylation near promoters and enhancers during embryonic stem cell self-renewal and differentiation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-01-27 | E-GEOD-53093 | biostudies-arrayexpress

ATF4 governs functional expansion of hematopoietic stem cells partially via Angptl3 in the fetal liver microenvironment

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-11-20 | E-GEOD-66382 | biostudies-arrayexpress

NRASG12V oncogene mediates self-renewal in acute myelogenous leukemia

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-11-16 | E-GEOD-49089 | biostudies-arrayexpress

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