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PDGFRβ+ cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny

ABSTRACT: Hematopoietic stem cell (HSC) generation in the aorta-gonads-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFRβ signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFRβ is involved. Here we show that PDGFRβ is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFRβ+ cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFRβ+ embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of these clinically important cells in vitro.

ORGANISM(S): Mus musculus

PROVIDER: GSE144837 | GEO | 2023/02/05

REPOSITORIES: GEO

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PDGFRβ+ cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny

Project description:Hematopoietic stem cell (HSC) generation in the aorta-gonads-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFRβ signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFRβ is involved. Here we show that PDGFRβ is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFRβ+ cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFRβ+ embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of these clinically important cells in vitro.

2022-07-19 | GSE162103 | GEO

Single cell RNA-Seq analysis of the human embryo dorsal aorta

Project description:Single cell RNA-Seq exploration of the human dorsal aorta, the hematopoietic stem cell (HSC) developmental niche, to explore heterogeneity of the HSC microenvironment and elucidate lineage trajectories of nascent hematopoietic stem/progenitor cells (HSPCs) from endothelium.

2020-09-17 | GSE151876 | GEO

Gene expression data from the mesenchymal stem cell line OP9M2 that supported expansion of human hematopoietic stem and progenitor cells in vitro

Project description:One of the long-standing goals in the field has been to establish a culture system that would allow maintenance of HSC properties ex vivo. In the absence of such system, the ability to model human hematopoiesis in vitro has been limited, and there has been little progress in the expansion of human HSCs for clinical application. To that end, we defined a mesenchymal stem cell co-culture system based on a monoclonal OP9 stromal cell line (OP9M2), for expansion of clonally multipotent human HSPCs that were protected from apoptosis and immediate differentiation, and retained the HSPC phenotype. To identify the supportive mechanisms, we performed a genome-wide gene expression analysis of OP9M2 stromal cells and compared the expression to a non-supportive stomal line (BFC012). This co-culture system provides a new, well-defined platform for studying mechanisms involved in HSC-niche interactions and protection of critical HSC properties ex vivo. To determine the cellular identity and the supportive mechanism of the OP9M2 cells, we compared the OP9M2 cells with non-supportive BFC012 stromal cells using Affymetrix mouse microarrays.

2013-01-31 | E-GEOD-34973 | biostudies-arrayexpress

A systems biology approach for defining the molecular framework of the hematopoietic stem cell niche

Project description:Hematopoietic stem/progenitor cells (HSPCs) 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. HSPCs 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 HSPC niches, we have compared the global transcriptome of HSPC-supportive and non/less-supportive stromal clones established from the AGM, FL and BM.

2014-03-01 | GSE44181 | GEO

MYCT1 CONTROLS ENVIRONMENTAL SENSING IN HUMAN HEMATOPOIETIC STEM CELLS

Project description:Hematopoietic stem cells (HSC) rely on a unique regulatory machinery that facilitates life-long blood production and enables reconstitution of the entire hematopoietic system upon transplantation. However, the biological processes governing human HSC self-renewal and engraftment ability are poorly understood and challenging to recapitulate ex vivo to facilitate robust human HSC expansion. We discovered a novel HSC regulatory protein, MYCT1 (MYCT target 1), that is selectively expressed in endothelial cells (EC) and undifferentiated human HSPCs but becomes drastically downregulated during HSC culture. Lentiviral knockdown of MYCT1 in human foetal liver and cord blood HSPCs revealed a critical role for MYCT1 in governing human HSPC expansion and engraftment ability. Single cell RNAseq of human CB HSPCs after MYCT1 knockdown and overexpression revealed that MYCT1 governs HSC functional competence and modulates cellular properties essential for HSC stemness, such as low mitochondrial metabolic activity. Indeed, restoring the compromised MYCT1 expression in cultured human CB HSPCs improved ex vivo expansion of the most undifferentiated human HSPCs and enhanced their engraftment ability. We found that MYCT1 is localized in the endosomal membrane and interacts with vesicle trafficking regulators and signalling machinery essential for HSC and EC function. Loss of MYCT1 led to excessive endocytosis and hyperactive signalling responses to cytokines, whereas restoring MYCT1 expression in cultured CB HSPCs balanced the abnormal endocytosis associated with prolonged culture and fine-tuned signalling responses. Our work identifies MYCT1-moderated endocytosis and environmental sensing as an essential regulatory mechanism required to preserve human HSC stemness, and pinpoints silencing of MYCT1 as a critical contributor to the dysfunction of cultured human HSCs that needs to be addressed to improve human HSC culture strategies.

2024-04-15 | PXD042257 | Pride

RNAseq analysis of hematopoietic stem cells isolated from control and Regnase1 null mice

Project description:The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder. HSPC fate is controlled by signals from the bone marrow niche resulting in alteration of the stem cell transcription network. Regnase-1, a member of the CCCH zinc finger protein family possessing RNAse activity, mediates post-transcriptional regulatory activity through degradation of target mRNAs. The precise function of Regnase-1 has been explored in inflammation-related cytokine expression but its function in hematopoiesis has not been elucidated. To clarify the role of Regnase-1 for hematopoiesis, we performed gene expression analysis on sorted HSC from control and Regnase1 null mice.

2019-01-25 | GSE125546 | GEO

Identification of osteolineage cell-derived extracellular vesicle cargo implicated in hematopoietic support

Project description:Osteolineage cell-derived extracellular vesicles (EVs) play a regulatory role in hematopoiesis and have been shown to promote the ex vivo expansion of human hematopoietic stem and progenitor cells (HSPCs). Here, we demonstrate that EVs from different human osteolineage sources do not have the same HSPC expansion promoting potential. Comparison of stimulatory and non-stimulatory osteolineage EVs by next-generation sequencing and mass spectrometry analyses revealed distinct microRNA and protein signatures identifying EV-derived candidate regulators of ex vivo HSPC expansion. Accordingly, the treatment of umbilical cord blood-derived CD34+ HSPCs with stimulatory EVs altered HSPC transcriptome, including genes with known roles in cell proliferation. An integrative bioinformatics approach, which connects the HSPC gene expression data with the candidate cargo in stimulatory EVs, delineated the potentially targeted biological functions and pathways during hematopoietic cell expansion and development. In conclusion, our study gives novel insights into the complex biological role of EVs in osteolineage cell-HSPC crosstalk and promotes the utility of EVs and their cargo as therapeutic agents in regenerative medicine.

2020-02-28 | PXD017172 | Pride

Pericyte-like cells generated from human pluripotent stem cells support hematopoietic stem and progenitors ex vivo

Project description:Various mesenchymal cell types have been identified as critical components of the hematopoietic stem/progenitor cell (HSPC) niche. Although several groups have described the generation of mesenchyme from human pluripotent stem cells (hPSC), the capacity of such cells to support hematopoiesis has not been reported. Here we have demonstrated that distinct mesenchymal subpopulations co-emerge from mesoderm during hPSC differentiation. Despite co-expression of common mesenchymal markers (CD73, CD105, CD90, PDGFRβ), a subset of cells defined as CD146++CD140alow supported functional HSPC ex vivo while CD146-CD140a+ cells drove differentiation. The CD146++ subset expressed genes associated with the HSPC niche and high levels of the Wnt inhibitors. HSPC support was contact-dependent and was mediated in part through JAG1 expression. Molecular profiling revealed remarkable transcriptional similarity between hPSC-derived CD146++ and primary human CD146++ perivascular cells. The derivation of diverse pools of mesenchymal populations from hPSC opens potential avenues to model their developmental and functional differences and to improve cell-based therapeutics from hPSC.

2018-03-07 | GSE83443 | GEO

The impact of remote solid tumors on bone marrow ecosystem at single-cell resolution

Project description:The bone marrow (BM) environment (BME) is inhabited by hematopoietic stem and progenitor cells (HSPCs) and niche cells, which are sources of bone homeostasis, hematopoiesis and immune response. The BM senses many pathological insults, including solid cancers. However, a comprehensive understanding of BM ecosystem response to solid cancer is lacking. Herein, by single-cell RNA sequencing, we characterized the BM landscape in tumor-bearing models prior to metastasis. We found that remote tumors induce dramatic systemic BM niche remodeling that drives HSPC reprogramming and dysfunctional hematopoiesis, which is distinct from innate immune responses.

2023-05-03 | GSE188648 | GEO

scRNA-seq of kidney marrow cells from Gata2b deficient and wild type zebrafish

Project description:GATA2 is a pivotal hematopoietic transcription factor required for generation and maintenance of hematopoietic stem cells (HSCs). Due to early embryonic lethality of Gata2 deficiency in mice, its role during adult hematopoiesis is incompletely understood. In zebrafish, mammalian functions of Gata2 are split between two orthologues: Gata2a and Gata2b. Previous studies have shown that Gata2b is prominently expressed in hematopoietic stem and progenitor cells (HSPCs), whereas Gata2a is mainly expressed in the vasculature. We found that Gata2b deficient zebrafish have a reduction in embryonic definitive HSPC numbers and have impaired myeloid lineage differentiation, but are viable. This allowed us to study the role of Gata2b in adult hematopoiesis. To assess the impact of Gata2b deficiency on the transcriptional profile of HSPCs and differentiated cells, we sorted the entire progenitor and HSPC population including the lymphoid population from kidney marrow (KM) of WT and germline Gata2b deficient zebrafish based on scatter profiles and processed for single-cell RNA sequencing. To enrich the scarce HSC population, we used pooled KM from two WT and Gata2b deficient Tg(CD41:GFP) zebrafish per sample and included all CD41:GFPlow expressing cells present in the kidney marrow pool as these cells were shown to contain transplantable HSCs.

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