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Iterative single cell analyses define the transcriptome of the first functional hematopoietic stem cells

ABSTRACT: Whereas hundreds of endothelial cells in the aorta-gonad-mesonephros (AGM) region transdifferentiate to hematopoietic cells, only 1-2 of these cells take on hematopoietic stem cell (HSC) identity at a single time point. Gata2 is one of a few transcription factors essential for HSC generation and function. In contrast to cell surface marker-based HSC enrichment approaches, enrichment based on Gata2 expression is directly linked to the internal regulatory network critical for HSC identity. Here we use index sorting of highly enriched Gata2-expressing intra-aortic hematopoietic cluster (IAHC) cells, iterative single cell transcriptomics and functional analyses to examine the relationship between HSC identity and expression of pivotal factors. Functional HSCs are enriched in Gata2 medium-expressing IAHC cells, which can be further subdivided based on Gata2, cKit and CD27 expression, where each subpopulation is not only associated with a specific molecular profile, but also distinct functionality in both in vitro and in vivo stem/progenitor assays. Immunohistochemical analysis localizes the first putative functional HSCs in vivo to small clusters in the AGM region, thus integrating molecular, functional and spatial information about the first cells in a mammalian embryo that acquire full HSC identity.

ORGANISM(S): Mus musculus

PROVIDER: GSE143637 | GEO | 2020/04/27

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from the AGM, FL and BM. Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive line from Fetal Calvaria (OP9) and non-supportive stromal clones from fetal liver (BFC). Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from fetal liver. We took advantage of stromal clones established from the AGM, FL and BM and tested for their ability to support or not HSCs ex vivo. RNA were extracted from confluent stromal cultures or sorted cells and used for hybridization of Affymetrix (mouse gene 1.0 ST) microarrays.

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Iterative single cell analyses define the transcriptome of the first functional hematopoietic stem cells

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