Volume 31, No 10, Oct 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 10, October 2021: 1106-1122   |  Open Access

ORIGINAL ARTICLES

Delineating spatiotemporal and hierarchical development of human fetal innate lymphoid cells

Chen Liu^1,† , Yandong Gong^2,† , Han Zhang^3,† , Hua Yang^4,† , Yang Zeng² , Zhilei Bian⁵ , Qian Xin¹ , Zhijie Bai¹ , Man Zhang¹ , Jian He¹ , Jing Yan¹ , Jie Zhou² , Zongcheng Li² , Yanli Ni² , Aiqing Wen^3,* , Yu Lan^5,* , Hongbo Hu^6,* , Bing Liu^1,2,5,8,*

¹State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China
²State Key Laboratory of Experimental Hematology, Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
³Department of Blood Transfusion, Daping Hospital, Army Military Medical University, Chongqing, China. 4 Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
⁴Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
⁵Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
⁶Center for Immunology and Hematology, the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University. Collaboration and Innovation Center for Biotherapy, Chengdu, China
^†These authors contributed equally: Chen Liu, Yandong Gong, Han Zhang, Hua Yang
⁸Lead contact. ✉email: dpyysxkwaq@hotmail.com; rainyblue_1999@126.com; hongbohu@scu.edu.cn; bingliu17@yahoo.com
Correspondence: Aiqing Wen(dpyysxkwaq@hotmail.com)Yu Lan(rainyblue_1999@126.com)Hongbo Hu(hongbohu@scu.edu.cn)Bing Liu(bingliu17@yahoo.com)

Whereas the critical roles of innate lymphoid cells (ILCs) in adult are increasingly appreciated, their developmental hierarchy in early human fetus remains largely elusive. In this study, we sorted human hematopoietic stem/progenitor cells, lymphoid progenitors, putative ILC progenitor/precursors and mature ILCs in the fetal hematopoietic, lymphoid and non-lymphoid tissues, from 8 to 12 post-conception weeks, for single-cell RNA-sequencing, followed by computational analysis and functional validation at bulk and single-cell levels. We delineated the early phase of ILC lineage commitment from hematopoietic stem/progenitor cells, which mainly occurred in fetal liver and intestine. We further unveiled interleukin-3 receptor as a surface marker for the lymphoid progenitors in fetal liver with T, B, ILC and myeloid potentials, while IL-3RA– lymphoid progenitors were predominantly B-lineage committed. Notably, we determined the heterogeneity and tissue distribution of each ILC subpopulation, revealing the proliferating characteristics shared by the precursors of each ILC subtype. Additionally, a novel unconventional ILC2 subpopulation (CRTH2– CCR9+ ILC2) was identified in fetal thymus. Taken together, our study illuminates the precise cellular and molecular features underlying the stepwise formation of human fetal ILC hierarchy with remarkable spatiotemporal heterogeneity.

https://doi.org/10.1038/s41422-021-00529-2

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