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 IGFBPS) 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.

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 G(o)ttgens;Cheng Li;Feng Liu

State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing,China;Institute for Stem Cell and Regeneration,Chinese Academy of Sciences,Beijing,China;University of Chinese Academy of Sciences,Beijing,China;School of Life Sciences,Center for Bioinformatics,Center for Statistical Science,Peking University,Beijing,China;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;State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing,China;CAS Key Laboratory of Genome Science & Information,Beijing Institute of Genomics,Chinese Academy of Sciences/China National Center for Bioinformation,Beijing,China;Beijing Key Laboratory of Genome and Precision Medicine Technologies,Beijing,China;Department of Human Anatomy,Histology,and Embryology,School of Basic Medical Sciences,Peking University,Beijing,China;Peking-Tsinghua Center for Life Sciences,Peking University,Beijing,China;BGI-ShenZhen,Shenzhen,Guangdong,China;Shenzhen Bay Laboratory,Shenzhen,Guangdong,China;Guangdong Provincial Key Laboratory of Genome Read and Write,Shenzhen,Guangdong,China;Department of Haematology,Wellcome-Medical Research Council Cambridge Stem Cell Institute,University of Cambridge,Cambridge,UK

细胞研究（英文版）

[1]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 G(o)ttgens;Cheng Li;Feng Liu-.Identification of HSC/MPP expansion units in fetal liver by single-cell spatiotemporal transcriptomics)[J].细胞研究（英文版）,2022(01):38-53

CD93,hepatoblasts,IGFBPS

Identification,expansion,units,fetal,liver,by,single,spatiotemporal,transcriptomics,Limited,knowledge,cellular,molecular,mechanisms,underlying,hematopoietic,stem,multipotent,progenitor,within,their,native,niche,has,impeded,application,therapies,hematological,malignancies,Here,constructed,transcriptome,map,mouse,FL,platform,hypothesis,generation,subsequent,experimental,validation,novel,regulatory,Single,revealed,three,transcriptionally,heterogeneous,subsets,among,which,enriched,exhibited,enhanced,properties,Moreover,employing,integrative,analysis,spatial,identified,pocket,like,PLUS,composed,cells,stromal,endothelial,macrophages,growth,factors,Unexpectedly,showed,fold,enrichment,Functionally,culture,assay,candidate,molecule,testing,respectively,validated,supportive,role,MDK,PTN,Finally,cross,species,functional,conserved,interactions,but,divergent,signatures,between,human,HSCs,MPPs,Taken,together,these,results,provide,essential,resource,understanding,development,insight,into,vivo

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