Identification of HSC/MPP expansion units in fetal liver by single-cell spatiotemporal transcriptomics
通过单细胞时空转录组学鉴定胎儿肝脏中的 HSC/MPP 扩增单位
単一細胞時空間トランスクリプトミクスによる胎児肝臓のHSC / MPP拡張ユニットの同定
단일 세포 시공간 전사체에 의한 태아 간에서 HSC/MPP 확장 단위 식별
Identificación de unidades de expansión HSC / MPP en hígado fetal mediante transcriptómica espacio-temporal unicelular
Identification des unités d'expansion HSC/MPP dans le foie fœtal par transcriptomique spatio-temporelle unicellulaire
Идентификация единиц экспансии HSC / MPP в печени плода с помощью одноклеточной пространственно-временной транскриптомики
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, 2 August 2021

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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