2. Academic Validation
  3. Fetal hepatocytes protect the HSPC genome via fetuin-A

Fetal hepatocytes protect the HSPC genome via fetuin-A

  • Nature. 2024 Dec 4. doi: 10.1038/s41586-024-08307-x.
Xiao-Lin Guo # 1,  Yi-Ding Wang # 1,  Yan-Jun Liu # 1,  Lei Chu 2,  Hua Zhu 3,  Ye Hu 1,  Ren-Yan Wu 1,  Hong-Yu Xie 1,  Juan Yu 4,  Shui-Ping Li 1,  Zhao-Yang Xiong 4,  Ruo-Yan Li 5,  Fang Ke 1,  Lei Chen 6,  Guo-Qiang Chen 1 7 8,  Liang Chen 9,  Fan Bai 5,  Tariq Enver 10,  Guo-Hong Li 4,  Huai-Fang Li 2,  Deng-Li Hong 11 12 13 14
Affiliations

Affiliations

  • 1 Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Institute of Haematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Obstetrics and Gynecology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
  • 3 Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 National laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 5 Biomedical Pioneering Innovation Centre (BIOPIC) and Translational Cancer Research Centre, School of Life Sciences, First Hospital, Peking University, Beijing, China.
  • 6 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8 Hainan Academy of Medical Sciences, School of Basic Medicine and Life Science, Hainan Medical University, Haikou, China.
  • 9 RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
  • 10 Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK.
  • 11 Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Institute of Haematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. dlhong@sjtu.edu.cn.
  • 12 Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China. dlhong@sjtu.edu.cn.
  • 13 Innovative Research Team of High-level Local Universities in Shanghai, Shanghai, China. dlhong@sjtu.edu.cn.
  • 14 Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China. dlhong@sjtu.edu.cn.
  • # Contributed equally.
PMID: 39633051 DOI: 10.1038/s41586-024-08307-x
Abstract

The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development1-3. Although numerous cell-intrinsic mechanisms have been revealed4-7, little is known about genome-protective effects and influences of developmental tissue microenvironments on tissue-forming cells. Here we show that fetal liver hepatocytes provide protection to haematopoietic stem and progenitor cell (HSPC) genomes. Lineage tracing and depletion in mice demonstrated that delayed hepatocyte development in early fetal livers increased the chromosomal instability of newly colonizing HSPCs. In addition, HSPCs developed tolerance to genotoxins in hepatocyte-conditioned medium, suggesting that hepatocytes protect the HSPC genome in a paracrine manner. Proteomic analyses demonstrated the enrichment of fetuin-A in hepatocyte-conditioned medium but not in early fetal livers. Fetuin-A activates a Toll-like Receptor pathway to prevent pathogenic R-loop accumulation in HSPCs undergoing DNA replication and gene transcription in the fetal liver. Numerous haematopoietic regulatory genes frequently involved in leukaemogenic mutations are associated with R-loop-enriched regions. In Fetua-knockout mice, HSPCs showed increased genome instability and susceptibility to malignancy induction. Moreover, low concentrations of fetuin-A correlated with the oncogenesis of childhood leukaemia. Therefore, we uncover a mechanism operating in developmental tissues that offers tissue-forming cell genome protection and is implicated in developmental-related diseases.

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