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Nature. 2016 May 26;533(7604):487-92. doi: 10.1038/nature17997. Epub 2016 May 18.

Tracing haematopoietic stem cell formation at single-cell resolution.

Zhou F1, Li X2, Wang W3, Zhu P2,4, Zhou J1, He W1, Ding M1, Xiong F1, Zheng X1, Li Z1, Ni Y1, Mu X3, Wen L2,5, Cheng T3,6, Lan Y7, Yuan W3, Tang F2,4,5,8, Liu B1,3,9.

Author information

State Key Laboratory of Proteomics, Translational Medicine Center of Stem Cells, 307-Ivy Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital, Academy of Military Medical Sciences, Beijing 100071, China.
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin 300020, China.
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China.
Collaborative Innovation Center for Cancer Medicine, National Institute of Biological Sciences, Tianjin 300020, China.
State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China.
Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China.
Institute of Hematology, Medical College of Jinan University, Guangzhou 510632, China.


Haematopoietic stem cells (HSCs) are derived early from embryonic precursors, such as haemogenic endothelial cells and pre-haematopoietic stem cells (pre-HSCs), the molecular identity of which still remains elusive. Here we use potent surface markers to capture the nascent pre-HSCs at high purity, as rigorously validated by single-cell-initiated serial transplantation. Then we apply single-cell RNA sequencing to analyse endothelial cells, CD45(-) and CD45(+) pre-HSCs in the aorta-gonad-mesonephros region, and HSCs in fetal liver. Pre-HSCs show unique features in transcriptional machinery, arterial signature, metabolism state, signalling pathway, and transcription factor network. Functionally, activation of mechanistic targets of rapamycin (mTOR) is shown to be indispensable for the emergence of HSCs but not haematopoietic progenitors. Transcriptome data-based functional analysis reveals remarkable heterogeneity in cell-cycle status of pre-HSCs. Finally, the core molecular signature of pre-HSCs is identified. Collectively, our work paves the way for dissection of complex molecular mechanisms regulating stepwise generation of HSCs in vivo, informing future efforts to engineer HSCs for clinical applications.

[Indexed for MEDLINE]

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