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Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium [RNA-seq]

ABSTRACT: Investigate the role of miR128 in the EHT process and the formation of nHSPCs

ORGANISM(S): Danio rerio Homo sapiens

PROVIDER: GSE210940 | GEO | 2023/05/24

REPOSITORIES: GEO

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Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium [scRNA-seq]

Project description:Investigate the role of miR128 in the EHT process and the formation of nHSPCs

2023-05-24 | GSE210941 | GEO

Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium.

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

2023-05-24 | GSE210942 | GEO

Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium.

Project description:Definitive haematopoietic stem and progenitor cells (HSPCs) generate erythroid, lymphoid and myeloid lineages. HSPCs are produced in the embryo via transdifferentiation of haemogenic endothelial cells in the aorta-gonad-mesonephros (AGM). HSPCs in the AGM are heterogeneous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. Here we discovered that loss of microRNA (miR)-128 in zebrafish leads to an expansion of HSPCs in the AGM with different cell cycle states and a skew towards erythroid and lymphoid progenitors. Manipulating miR-128 in differentiating haemogenic endothelial cells, before their transition to HSPCs, recapitulated the lineage skewing in both zebrafish and human pluripotent stem cells. miR-128 promotes Wnt and Notch signalling in the AGM via post-transcriptional repression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b. De-repression of cskn1a1 resulted in replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in G2/M and lymphoid-biased HSPCs with long-term consequence on the respective blood lineages. We propose that HSPC heterogeneity arises in the AGM endothelium and is programmed in part by Wnt and Notch signalling.

| S-EPMC10415179 | biostudies-literature

Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium.

Project description:Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium.

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Chemically-defined generation of human hemogenic endothelium and definitive hematopoietic progenitor cells.

Project description:Human hematopoietic stem cells (HSCs), which arise from aorta-gonad-mesonephros (AGM), are widely used to treat blood diseases and cancers. However, a technique for their robust generation in vitro is still missing. Here we show temporal manipulation of Wnt signaling is sufficient and essential to induce AGM-like hematopoiesis from human pluripotent stem cells. TGFβ inhibition at the stage of aorta-like SOX17+CD235a- hemogenic endothelium yielded AGM-like hematopoietic progenitors, which closely resembled primary cord blood HSCs at the transcriptional level and contained diverse lineage-primed progenitor populations via single cell RNA-sequencing analysis. Notably, the resulting definitive cells presented lymphoid and myeloid potential in vitro; and could home to a definitive hematopoietic site in zebrafish and rescue bloodless zebrafish after transplantation. Engraftment and multilineage repopulating activities were also observed in mouse recipients. Together, our work provided a chemically-defined and feeder-free culture platform for scalable generation of AGM-like hematopoietic progenitor cells, leading to enhanced production of functional blood and immune cells for various therapeutic applications.

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Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium [scRNA-seq]

Project description:Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium [scRNA-seq]

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Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium [RNA-seq]

Project description:Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium [RNA-seq]

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Sequential regulation of hemogenic fate and hematopoietic stem and progenitor cell formation from arterial endothelium by Ezh1/2.

Project description:Across species, hematopoietic stem and progenitor cells (HSPCs) arise during embryogenesis from a specialized arterial population, termed hemogenic endothelium. Here, we describe a mechanistic role for the epigenetic regulator, Enhancer of zeste homolog-1 (Ezh1), in vertebrate HSPC production via regulation of hemogenic commitment. Loss of ezh1 in zebrafish embryos favored acquisition of hemogenic (gata2b) and HSPC (runx1) fate at the expense of the arterial program (ephrinb2a, dll4). In contrast, ezh1 overexpression blocked hematopoietic progression via maintenance of arterial gene expression. The related Polycomb group subunit, Ezh2, functioned in a non-redundant, sequential manner, whereby inhibition had no impact on arterial identity, but was capable of blocking ezh1-knockdown-associated HSPC expansion. Single-cell RNA sequencing across ezh1 genotypes revealed a dropout of ezh1+/- cells among arterial endothelium associated with positive regulation of gene transcription. Exploitation of Ezh1/2 modulation has potential functional relevance for improving in vitro HSPC differentiation from induced pluripotent stem cell sources.

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SAHA Enhances Differentiation of CD34+CD45+ Hematopoietic Stem and Progenitor Cells from Pluripotent Stem Cells Concomitant with an Increase in Hemogenic Endothelium.

Project description:Epigenetic modification is an important process during hematopoietic cell differentiation. Histone deacetylase (HDAC) inhibitors have previously been shown to enhance expansion of umbilical cord blood-derived hematopoietic stem cells (HSCs). However, the effect of HDAC inhibitors on pluripotent stem cells (PSCs) in this context is less understood. For years, investigators have considered PSC-derived natural killer (NK) and T-cell therapies. These "off-the-shelf" cellular therapies are now entering the clinic. However, the in vitro commitment of PSCs to the hematopoietic lineage is inefficient and represents a major bottleneck. We investigated whether HDAC inhibitors (HDACi) influence human PSC differentiation into CD34+CD45+ hematopoietic stem and progenitor cells (HSPCs), focusing on hemogenic endothelium (HE). Pluripotent stem cells cultured in the presence of HDACi showed a 2-5 times increase in HSPCs. Concurrent with this, HDACi-treated PSCs increased expression of 7 transcription factors (HOXA5, HOXA9, HOXA10, RUNX1, ERG, SPI1, and LCOR) recently shown to convert HE to HSPCs. ChIP-qPCR showed that SAHA upregulated acetylated-H3 at the promoter region of the above key genes. SAHA-treated human PSC-derived CD34+CD45+ cells showed primary engraftment in immunodeficient mice, but not serial transplantation. We further demonstrate that SAHA-derived HSPCs could differentiate into functional NK cells in vitro. The addition of SAHA is an easy and effective approach to overcoming the bottleneck in the transition from PSC to HSPCs for "off-the-shelf" cellular immunotherapy.

| S-EPMC9154343 | biostudies-literature

GATA2 is Dispensable for Generation of Hemogenic Endothelium But Required for Endothelial-to-Hematopoietic Transition

Project description:Using loss-of- and restoration-of-function approaches, we found that GATA2 function is mainly focused on enthothelial-to-hematopoietic transition (EHT) other than formation of hemogenic endothelial cells (HECs) in hematopoietic development of human ESCs. In addition, our study found that small portion of hematopoietic progenitors (HPs) can be generated even in the absence of GATA, which was proved to have similar character to that of GATA2-independent HPs lacking CFU-G and CFU-GM potential but retaining lymphoid potential.

2018-05-17 | GSE102767 | GEO

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