My research interest is to unravel the cellular and molecular basis underpinning fate decision of erythroid (Ery) and megakaryocytic (Mk) lineages and their related disorders. By developing and applying single-cell transcriptome profiling with parallel mutation detection, we demonstrated that JAK2-mutant Mk-primed HSCs serve as the cellular origin of JAK2V617F+ essential thrombocythemia. Upon treatment, JAK2-mutant Mk-primed HSCs are preferentially targeted with homozygous ones compelled to re-enter quiescence whereas heterozygous counterparts undergone apoptosis. Our study provides important evidence to link stem cell heterogeneity with the pathogenesis and therapeutic response of a malignant disease. As HSC heterogeneity underlies the disparate phenotypes of MPNs harboring the same initiating mutation, malignant transformation of neoplasms might involve a specific subset of stem cells within a heterogeneous stem cell population. Next, to investigate the cellular origin of children MPNs, we traced the fate decision of Ery- and Mk- lineage during human embryonic hematopoiesis and identified GPA+ Ery- and THBS1+ Mk-primed hemogenic endothelial cells, suggesting that the fate decision between Ery and Mk lineage could emerge at hemogenic endothelial stage. This observation also raised an intriguing possibility that lineage-biased hemogenic endothelial cells with driver mutations might be the initiators of children MPNs. Along the lineage differentiation, we further deciphered the heterogeneity of erythroid progenitor cells. In its related disease Diamond-Blankfan anemia, we found the conflict between inherent fast cell cycle and deficient ribosome biogenesis in erythroid progenitors underlies the pathogenesis of DBA, while the therapeutic efficacy of glucocorticoid primarily leads from the inhibition of cell cycle progression via induction of the type 1 interferon pathway, suggesting that interferon administration may constitute a new alternative therapeutic strategy for the treatment of DBA. The trial was registered at www.chictr.org.cn as ChiCTR2000038510. These scientific findings were published on high-profile journals such as Nature Immunology, Cell Stem Cell (2021a, 2021b, 2025)，Nature Communications (2018, 2021,2024)，Developmental Cell，EMBO reports, eLife, etc. In the commentary published in the Cell Stem Cell, the leading scientists in the field highlighted our studies provide several potentially seminal observations that have important implications in development, regeneration as well as disease pathogenesis.
Ph.D., Physiology, Institute of Zoology, Chinese Academic of Sciences, Beijing, China, 2003-2008
B.S., Biology, Shaanxi Normal University, Xi'an, China, 1998-2002
Deputy Director and Research Investigator, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 2022-
Research Investigator, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 2014-2022
Post-doctoral Research, Cell and developmental Biology, University of Michigan Medical School, 2008-2014
PRINCIPAL HONORS, AWARDS:
2023 Medical Talents of Tianjin
2022 National Science Fund for Distinguished Young Scholars
2022 Top Ten Research Advances in Hematology in China
2021 Top Ten Research Advances in Hematology in China
2020 Top Ten Research Advances in Hematology in China
2015 The first-level personnel of the "131" Talent Program in Tianjin City
2014 Tianjin Innovation Talents Promotion Program Young Excellent Science and Technology Talent
2012-2013 American Heart Association (AHA) Midwest 3rd year post-doctoral fellowship
2010-2012 American Heart Association (AHA) Midwest post-doctoral fellowship
MAJOR NATIONAL LEADERSHIP POSITIONS, SOCIETIES AND BOARDS:
2024-2029 Vice Director, The Tenth Experimental Hematology Professional Committee of the Chinese Society of Pathophysiology
2023-2027 Secretary, The Professional Committee of Hematological Physiology of the Chinese Physiology Society
2023-2028 Deputy Secretary General, The Third Council of the Tianjin Society of Biology
2024-2026 Editorial Board Member, Fundamental Research
2021-2026 Vice President of the Council, Tianjin Society of Blood and Regenerative Medicine
2020-Deputy Section Editor, CELL & TISSUE RESEARCH
SELECTED PUBLICATIONS:
1. Changlu Xu#, Jian He#, Hongtao Wang#, Yingnan Zhang#, Jing Wu#, Lu Zhao#, Yue Li, Jie Gao, Guangfeng Geng, Bingrui Wang, Xiaoyuan Chen, Zhaofeng Zheng, Biao Shen, Yang Zeng, Zhijie Bai, Hua Yang, Shujuan Shi, Fang Dong, Shihui Ma, Erlie Jiang, Tao Cheng, Yu Lan*, Jiaxi Zhou*, Bing Liu*, Lihong Shi*. Single-cell transcriptomic analysis identifies an immune-prone population in erythroid precursors during human ontogenesis. Nature Immunology. 2022 Jul;23(7):1109-1120.
2. Weili Liu#*, Xiaoru Zhang#, Jinhua Liu#, Lingling Pu#, Lanlan Ai, Hongbao Xu, Guangrui Wang, Ding Wang, Xiaona Song, Yingnan Zhang, Ling Zhang, Jie Gao, Xiaoling Cheng, Xinxing Wang, Jingyuan Tong, Xiaowei Xie, Fang Dong, Yingchi Zhang, Ping Zhu, Zhaoli Chen*, Peng Wu*, Lihong Shi*. An erythroid-biased FOShi hematopoietic multipotent progenitor subpopulation contributes to adaptation to chronic hypoxia. Cell Stem Cell. 2025 Apr 5: Online ahead of print.
3. Jingyuan Tong#, Ting Sun#, Shihui Ma#, Yanhong Zhao#, Mankai Ju#, Yuchen Gao, Ping Zhu, Puwen Tan, Rongfeng Fu, Anqi Zhang, Ding Wang, Di Wang, Zhijian Xiao, Jiaxi Zhou, Renchi Yang, Stephen J. Loughran, Juan Li, Anthony R. Green, Emery H. Bresnick, Dong Wang,* Tao Cheng,*Lei Zhang,* and Lihong Shi*. Hematopoietic Stem Cell Heterogeneity Is Linked to the Initiation and Therapeutic Response of Myeloproliferative Neoplasms. Cell Stem Cell. 2021. 28(3): 502–513.
4. Jing Liang #, Yang Wan #, Jie Gao #, Lingyue Zheng #, Jingwei Wang, Peng Wu, Yue Li, Bingrui Wang, Ding Wang, Yige Ma, Biao Shen, Xue Lv, Di Wang, Na An, Xiaoli Ma, Guangfeng Geng, Jingyuan Tong, Jinhua Liu, Guo Chen, Meng Gao, Ryo Kurita, Yukio Nakamura, Ping Zhu, Hang Yin, Xiaofan Zhu*, Lihong Shi*. Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia. Nature Communications. 2024 Jul 6;15(1):5678.
5. Hongtao Wang#, Jian He#, Changlu Xu#, Xiaoyuan Chen#, Hua Yang#, Shujuan Shi, Cuicui Liu, Yang Zeng, Dan Wu, Zhijie Bai, Mengge Wang, Yuqi Wen, Pei Su, Meijuan Xia, Baiming Huang, Chunyu Ma, Lihong Bian, Yu Lan, Tao Cheng, Lihong Shi,* Bing Liu,* and Jiaxi Zhou*. Decoding Human Megakaryocyte Development. Cell Stem Cell. 2021. 28(3):535-549.e8
6. Bingrui Wang#, Chenchen Wang#, Yang Wan#, Jie Gao#, Yige Ma, Yingnan Zhang, Jingyuan Tong, Yingchi Zhang, Jinhua Liu, Lixian Chang, Changlu Xu, Biao Shen, Yumei Chen, Erlie Jiang, Ryo Kurita, Yukio Nakamura, Kim-Chew Lim, James Douglas Engel, Jiaxi Zhou, Tao Cheng*, Xiaofan Zhu*, Ping Zhu* and Lihong Shi*. Decoding the pathogenesis of Diamond–Blackfan anemia using single-cell RNA-seq. Cell Discovery. 2022 May 10;8(1):41.
7. Yanni Ma#, Siqi Liu#, Jie Gao#, Chunyan Chen#, Xin Zhang#, Hao Yuan, Zhongyang Chen, Xiaolin Yin, Chenguang Sun, Yanan Mao, Fanqi Zhou, Yi Shao, Qian Liu, Jiayue Xu, Li Cheng, Daqi Yu, Pingping Li,Ping Yi, Jiahuan He, Guangfeng Geng, Qing Guo, Yanmin Si, Hualu Zhao, Haipeng Li, Graham L. Banes, He Liu, Yukio Nakamura, Ryo Kurita, Yue Huang, Xiaoshuang Wang, Fang Wang, Gang Fang, James Douglas Engel, Lihong Shi,* Yong E. Zhang,* and Jia Yu*.Genome-wide analysis of pseudogenes reveals HBBP1’s human-specific essentiality in erythropoiesis and implication in b-thalassemia. Developmental Cell. 2021, Feb 22; 56(4):478-493.
8. Guangfeng Geng#, Jinhua Liu#, Changlu Xu#, Yandong Pei, Linbo Chen, Chenglong Mu, Ding Wang, Jie Gao, Yue Li, Jing Liang, Tian Zhao, Chuanmei Zhang, Jiaxi Zhou, Quan Chen*, Yushan Zhu*, Lihong Shi* Receptor-mediated mitophagy regulates EPO production and protects against renal anemia. Elife. 2021 10, e64480.
9. Yapu Li#, Ding Wang#, Hongtao Wang#, Xin Huang, Yuqi Wen, BingRui Wang, Changlu Xu,Jie Gao, Jinhua Liu, Jingyuan Tong, Mengge Wang, Pei Su, Sirui Ren, Feng Ma, Hong-Dong Li, Emery H Bresnick, Jiaxi Zhou,* & Lihong Shi,* A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells. EMBO Reports. 2021 Jan 7;22(1):e50535.
10. Hongtao Wang, Mengge Wang, Yuqi Wen, Changlu Xu, Xiaoyuan Chen, Dan Wu, Pei Su, Wen Zhou, Tao Cheng, Lihong Shi*, Jiaxi Zhou* Biphasic Regulation of Mesenchymal Genes Controls Fate Switches During Hematopoietic Differentiation of Human Pluripotent Stem Cells. Advanced Science. 2020 Aug 19;7(20):2001019.