Identification of HSC/MPP Expansion Units in Fetal Liver by Single-cell Spatiotemporal Transcriptomics

Overview

Journal Cell Res

Specialty Cell Biology

Date 2021 Aug 3

PMID 34341490

Citations 40

Authors

Suwei Gao

Qiang Shi

Yifan Zhang

Guixian Liang

Zhixin Kang

Baofeng Huang

Dongyuan Ma

Lu Wang

Jianwei Jiao

Xiangdong Fang

Cheng-Ran Xu

Longqi Liu

Xun Xu

Berthold Gottgens

Cheng Li

Feng Liu

Affiliations

Soon will be listed here.

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.

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