| Literature DB >> 34341490 |
Suwei Gao1,2,3, Qiang Shi4, Yifan Zhang1,2,3, Guixian Liang1,2,3, Zhixin Kang1,2,3, Baofeng Huang1,2,3, Dongyuan Ma1,2, Lu Wang5, Jianwei Jiao2,3,6, Xiangdong Fang2,3,7,8, Cheng-Ran Xu9,10, Longqi Liu11,12, Xun Xu11,13, Berthold Göttgens14, Cheng Li15, Feng Liu16,17,18.
Abstract
Limited knowledge of cellular and molecular mechanisms underlying hematopoietic stem cell and multipotent progenitor (HSC/MPP) expansion within their native niche has impeded the application of stem cell-based therapies for hematological malignancies. Here, we constructed a spatiotemporal transcriptome map of mouse fetal liver (FL) as a platform for hypothesis generation and subsequent experimental validation of novel regulatory mechanisms. Single-cell transcriptomics revealed three transcriptionally heterogeneous HSC/MPP subsets, among which a CD93-enriched subset exhibited enhanced stem cell properties. Moreover, by employing integrative analysis of single-cell and spatial transcriptomics, we identified novel HSC/MPP 'pocket-like' units (HSC PLUS), composed of niche cells (hepatoblasts, stromal cells, endothelial cells, and macrophages) and enriched with growth factors. Unexpectedly, macrophages showed an 11-fold enrichment in the HSC PLUS. Functionally, macrophage-HSC/MPP co-culture assay and candidate molecule testing, respectively, validated the supportive role of macrophages and growth factors (MDK, PTN, and IGFBP5) in HSC/MPP expansion. Finally, cross-species analysis and functional validation showed conserved cell-cell interactions and expansion mechanisms but divergent transcriptome signatures between mouse and human FL HSCs/MPPs. Taken together, these results provide an essential resource for understanding HSC/MPP development in FL, and novel insight into functional HSC/MPP expansion ex vivo.Entities:
Mesh：
Year: 2021 PMID： 34341490 PMCID： PMC8724330 DOI： 10.1038/s41422-021-00540-7
Source DB: PubMed Journal: Cell Res ISSN： 1001-0602 Impact factor: 25.617