PubCard - Identification of HSC/MPP expansion units in fetal liver by single-cell spatiotemporal transcriptomics

(Peer-Reviewed) Identification of HSC/MPP expansion units in fetal liver by single-cell spatiotemporal transcriptomics

Suwei Gao 高素伟 ¹ ² ³, Qiang Shi ⁴, Yifan Zhang 张一帆 ¹ ² ³, Guixian Liang 梁桂仙 ¹ ² ³, Zhixin Kang 康志鑫 ¹ ² ³, Baofeng Huang 黄宝凤 ¹ ² ³, Dongyuan Ma 马东媛 ¹ ², Lu Wang 王璐 ⁵, Jianwei Jiao 焦建伟 ² ³ ⁶, Xiangdong Fang ² ³ ⁷ ⁸, Cheng-Ran Xu ⁹ ¹⁰, Longqi Liu ¹¹ ¹², Xun Xu 徐讯 ¹¹ ¹³, Berthold Göttgens ¹⁴, Cheng Li 李程 ⁴, Feng Liu 刘峰 ¹ ² ³

¹ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China 中国科学院动物研究所膜生物学国家重点实验室
² Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China 中国科学院干细胞与再生医学创新研究院
³ University of Chinese Academy of Sciences, Beijing, China 中国科学院大学
⁴ School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China 北京大学生命科学学院统计科学中心生物信息中心
⁵ State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China 中国医学科学院北京协和医学院血液学研究所实验血液学国家重点实验室
⁶ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China 中国科学院动物研究所干细胞与生殖生物学国家重点实验室
⁷ CAS Key Laboratory of Genome Science & Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China 中国科学院北京基因组研究所国家生物信息中心基因组科学与信息重点实验室
⁸ Beijing Key Laboratory of Genome and Precision Medicine Technologies, Beijing, China 基因组与精准医学检测技术北京市重点实验室
⁹ Department of Human Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Peking University, Beijing, China 北京大学基础医学院人体解剖与组织胚胎学系
¹⁰ Peking–Tsinghua Center for Life Sciences, Peking University, Beijing, China 清华大学-北京大学生命科学联合中心
¹¹ BGI-ShenZhen, Shenzhen, Guangdong, China 深圳华大生命科学研究院
¹² Shenzhen Bay Laboratory, Shenzhen, Guangdong, China 深圳湾实验室
¹³ Guangdong Provincial Key Laboratory of Genome Read and Write, Shenzhen, Guangdong, China 广东省高通量基因组测序与合成编辑重点实验室
¹⁴ Department of Haematology, Wellcome-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

Cell Research, 2021-08-02

https://doi.org/10.1038/s41422-021-00540-7

https://www.nature.com/articles/s41422-021-00540-7

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.