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

作　　者：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 

机构地区：[1]State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing,China [2]Institute for Stem Cell and Regeneration,Chinese Academy of Sciences,Beijing,China [3]University of Chinese Academy of Sciences,Beijing,China [4]School of Life Sciences,Center for Bioinformatics,Center for Statistical Science,Peking University,Beijing,China [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 [6]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing,China [7]CAS Key Laboratory of Genome Science&Information,Beijing Institute of Genomics,Chinese Academy of Sciences/China National Center for Bioinformation,Beijing,China [8]Beijing Key Laboratory of Genome and Precision Medicine Technologies,Beijing,China [9]Department of Human Anatomy,Histology,and Embryology,School of Basic Medical Sciences,Peking University,Beijing,China [10]Peking–Tsinghua Center for Life Sciences,Peking University,Beijing,China [11]BGI-ShenZhen,Shenzhen,Guangdong,China [12]Shenzhen Bay Laboratory,Shenzhen,Guangdong,China [13]Guangdong Provincial Key Laboratory of Genome Read and Write,Shenzhen,Guangdong,China [14]Department of Haematology,Wellcome-Medical Research Council Cambridge Stem Cell Institute,University of Cambridge,Cambridge,UK

出　　处：《Cell Research》2022年第1期38-53,共16页细胞研究（英文版）

基　　金：supported by grants from the National Key R&D Program of China(2018YFA0800200,2018YFA0801000,2016YFA0100500 to F.L.,and 2016YFA0100103 to C.L.);the Strategic Priority Research Program of the Chinese Academy of Sciences,China(XDA16010207 to F.L.);the National Natural Science Foundation of China(31830061,81530004,31425016 to F.L.,and 31871266 to C.L.);NSFC Key Research Grant 71532001(to C.L.).

摘　　要：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.

关 键 词：FETAL EXPANSION HSC 

分 类 号：R321.5[医药卫生—人体解剖和组织胚胎学]