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Self-renewal and differentiation dynamics of native hematopoietic stem and progenitor cells at single-cell resolution

ABSTRACT: Hematopoiesis has a long track record of embracing single-cell functional and molecular profiling technologies. However, a single-cell resolution quantitative model of native hematopoiesis has never been reported. Here, we employ persistent labelling of stem cells combined with time-series single-cell RNA-Seq (scRNA-Seq) to build the first quantitative model of the native blood stem and progenitor dynamics in the mouse bone marrow at single-cell resolution. We capture compartment-wide flux and net proliferation rates in real-time, thus revealing the distinct ways in which different blood lineages maintain their cellular output. By exploring the molecular layers of scRNA-Seq, we pinpoint molecular changes associated with changes in cell behavior, such as increased differentiation or growth rates. Finally, unlike immunophenotyping data, our model can easily be integrated with external data. This enabled quantitative comparison between homeostatic and transplantation conditions which highlighted lineages and specific stages within them with up-regulated differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE207412 | GEO | 2023/06/20

REPOSITORIES: GEO

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Project description:Native bone marrow mesenchymal stem/stromal cells (BM-MSCs) participate in generating and shaping the skeleton and bone marrow throughout the lifespan. Moreover, BM-MSCs regulate hematopoiesis by contributing to the hematopoietic stem cell niche in providing critical cytokines, chemokines and extracellular matrix components. However, BM-MSCs per se contain a heterogeneous cell population that remains ill-defined. Although studies on the taxonomy of native BM-MSCs in mice have just started to emerge, the taxonomy of native human BM-MSCs remains unelucidated. By using single-cell RNA sequencing (scRNA-seq), we aimed to define a proper taxonomy for native human BM non-hematopoietic subsets including endothelial cells (ECs) and mural cells (MCs) but with a focal point on MSCs. To this end, transcriptomic scRNA-seq data were generated from 5 distinct BM donors and were analyzed together with other transcriptomic data and with bioinformatics analyses at different levels to identify, characterize and classify distinct native subsets with relevant biomarkers. We could ascribe novel specific biomarkers to ECs, MCs and MSCs. Unlike ECs and MCs, MSCs exhibited an adipogenic transcriptomic pattern while co-expressing genes related to hematopoiesis support and multilineage commitment potential. Furthermore, by a comparative analysis of scRNA-seq of BM cells from humans and mice, we identified core genes conserved in both species. Notably, we identified MARCKS, CXCL12, PDGFRA, and LEPR together with adipogenic factors as archetypal biomarkers to reveal native MSCs within BM. In addition, our data suggest some complex gene nodes regulating critical biological functions of native BM-MSCs together with a preferential commitment toward an adipocyte lineage. Overall, our taxonomy for native BM non-hematopoietic compartment provides an explicit depiction of gene expression in human ECs, MCs and MSCs at single-cell resolution. This analysis helps enhance our understanding of the phenotype and the complexity of biological functions of native human BM-MSCs.

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Self-renewal and differentiation dynamics of native hematopoietic stem and progenitor cells at single-cell resolution

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