Fetal hepatocytes protect the HSPC genome via fetuin-A

Xiao-Lin Guo, Yi-Ding Wang, Yan-Jun Liu, Lei Chu, Hua Zhu, Ye Hu, Ren-Yan Wu, Hong-Yu Xie, Juan Yu, Shui-Ping Li, Chao-Yang Xiong, Ruo-Yan Li, Fang Ke, Lei Chen, Guo-Qiang Chen, Liang Chen, Fan Bai, Tariq Enver, Guo-Hong Li, Huai-Fang Li and Deng-Li Hong ()
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Xiao-Lin Guo: Shanghai Jiao Tong University School of Medicine
Yi-Ding Wang: Shanghai Jiao Tong University School of Medicine
Yan-Jun Liu: Shanghai Jiao Tong University School of Medicine
Lei Chu: Tongji University School of Medicine
Hua Zhu: Shanghai Jiao Tong University School of Medicine
Ye Hu: Shanghai Jiao Tong University School of Medicine
Ren-Yan Wu: Shanghai Jiao Tong University School of Medicine
Hong-Yu Xie: Shanghai Jiao Tong University School of Medicine
Juan Yu: Chinese Academy of Sciences
Shui-Ping Li: Shanghai Jiao Tong University School of Medicine
Chao-Yang Xiong: Chinese Academy of Sciences
Ruo-Yan Li: Peking University
Fang Ke: Shanghai Jiao Tong University School of Medicine
Lei Chen: Shanghai Jiao Tong University School of Medicine
Guo-Qiang Chen: Shanghai Jiao Tong University School of Medicine
Liang Chen: Wuhan University
Fan Bai: Peking University
Tariq Enver: University College London
Guo-Hong Li: Chinese Academy of Sciences
Huai-Fang Li: Tongji University School of Medicine
Deng-Li Hong: Shanghai Jiao Tong University School of Medicine

Nature, 2025, vol. 637, issue 8045, 402-411

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08307-x

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