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Cell stem cell
10 04, 2018;23 (4): 599-614.e4.

Single-Cell RNA Sequencing Analysis Reveals Sequential Cell Fate Transition during Human Spermatogenesis.

Mei Wang, Xixi Liu, Gang Chang, Yidong Chen, Geng An, Liying Yan, Shuai Gao, Yanwen Xu, Yueli Cui, Ji Dong, Yuhan Chen, Xiaoying Fan, Yuqiong Hu, Ke Song, Xiaohui Zhu, Yun Gao, Zhaokai Yao, Shuhui Bian, Yu Hou, Jiahao Lu, Rui Wang, Yong Fan, Ying Lian, Wenhao Tang, Yapeng Wang, Jianqiao Liu, Lianming Zhao, Luyu Wang, Zhaoting Liu, Renpei Yuan, Yujia Shi, Boqiang Hu, Xiulian Ren, Fuchou Tang, Xiao-Yang Zhao, Jie Qiao
Author Information
  1. Mei Wang: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC.
  2. Xixi Liu: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  3. Gang Chang: Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, Guangdong 518060, PRC.
  4. Yidong Chen: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, PRC.
  5. Geng An: Reproductive Medicine Center of The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PRC.
  6. Liying Yan: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  7. Shuai Gao: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  8. Yanwen Xu: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC.
  9. Yueli Cui: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  10. Ji Dong: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  11. Yuhan Chen: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC.
  12. Xiaoying Fan: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  13. Yuqiong Hu: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, PRC.
  14. Ke Song: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC.
  15. Xiaohui Zhu: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  16. Yun Gao: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  17. Zhaokai Yao: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC.
  18. Shuhui Bian: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, PRC.
  19. Yu Hou: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  20. Jiahao Lu: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC.
  21. Rui Wang: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  22. Yong Fan: Reproductive Medicine Center of The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PRC.
  23. Ying Lian: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  24. Wenhao Tang: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  25. Yapeng Wang: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  26. Jianqiao Liu: Reproductive Medicine Center of The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PRC.
  27. Lianming Zhao: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  28. Luyu Wang: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  29. Zhaoting Liu: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC.
  30. Renpei Yuan: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  31. Yujia Shi: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC.
  32. Boqiang Hu: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  33. Xiulian Ren: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC.
  34. Fuchou Tang: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Peking University, Beijing 100191, PRC; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, PRC. Electronic address: tangfuchou@pku.edu.cn.
  35. Xiao-Yang Zhao: Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PRC; Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong 510515, PRC. Electronic address: zhaoxiaoyang@smu.edu.cn.
  36. Jie Qiao: Department of Obstetrics and Gynecology, Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, PRC; Biomedical Pioneering Innovation Center and Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, PRC; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, PRC. Electronic address: jie.qiao@263.net.
PMID: 30174296 DOI: 10.1016/j.stem.2018.08.007

Abstract

Spermatogenesis generates mature male gametes and is critical for the proper transmission of genetic information between generations. However, the developmental landscapes of human spermatogenesis remain unknown. Here, we performed single-cell RNA sequencing (scRNA-seq) analysis for 2,854 testicular cells from donors with normal spermatogenesis and 174 testicular cells from one nonobstructive azoospermia (NOA) donor. A hierarchical model was established, which was characterized by the sequential and stepwise development of three spermatogonia subtypes, seven spermatocyte subtypes, and four spermatid subtypes. Further analysis identified several stage-specific marker genes of human germ cells, such as HMGA1, PIWIL4, TEX29, SCML1, and CCDC112. Moreover, we identified altered gene expression patterns in the testicular somatic cells of one NOA patient via scRNA-seq analysis, paving the way for further diagnosis of male infertility. Our work allows for the reconstruction of transcriptional programs inherent to sequential cell fate transition during human spermatogenesis and has implications for deciphering male-related reproductive disorders.

Keywords

human spermatogenesis single-cell RNA sequencing

MeSH Term

Cell Lineage
Cells, Cultured
Computational Biology
Humans
Male
Sequence Analysis, RNA
Single-Cell Analysis
Spermatogenesis
Spermatozoa
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

BioProject: PRJCA005394 (single cell RNA-seq of human spermatogenesis)

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