上海交通大学医学院洪登礼研究团队报道，胎儿肝细胞通过Fetuin-A保护HSPC基因组。相关论文于2024年12月4日发表在《自然》杂志上。

研究人员表示，在胚胎发育过程中，快速增殖细胞基因组完整性的维持是一个重大挑战。虽然已经揭示了许多细胞内在机制，但关于发育组织微环境对组织形成细胞的基因组保护作用和影响知之甚少。

本研究表明，胎儿肝细胞对造血干细胞和祖细胞（HSPC）基因组提供保护。小鼠的谱系追踪和耗尽表明，早期胎儿肝脏中肝细胞发育的延迟增加了新定植的HSPCs的染色体不稳定性。此外，HSPC在肝细胞条件培养基中对基因毒素产生耐受性，表明肝细胞以旁分泌方式保护HSPC基因组。

蛋白质组学分析表明，Fetuin-A在肝细胞条件培养基中富集，但在早期胎儿肝脏中不富集。Fetuin-A激活toll样受体通路，阻止胎儿肝脏中进行DNA复制和基因转录的HSPCs的致病性R-环积累。许多经常参与致白血病突变的造血调节基因与R-环富集区有关。在fetua基因敲除小鼠中，HSPCs表现出增加的基因组不稳定性和对恶性肿瘤诱导的易感性。

此外，低浓度的Fetuin-A与儿童白血病的癌变有关。因此，小组发现了一种在发育组织中运作的机制，该机制提供组织形成细胞基因组保护，并与发育相关疾病有关。

附：英文原文

Title: Fetal hepatocytes protect the HSPC genome via fetuin-A

Author: Guo, Xiao-Lin, Wang, Yi-Ding, Liu, Yan-Jun, Chu, Lei, Zhu, Hua, Hu, Ye, Wu, Ren-Yan, Xie, Hong-Yu, Yu, Juan, Li, Shui-Ping, Xiong, Zhao-Yang, Li, Ruo-Yan, Ke, Fang, Chen, Lei, Chen, Guo-Qiang, Chen, Liang, Bai, Fan, Enver, Tariq, Li, Guo-Hong, Li, Huai-Fang, Hong, Deng-Li

Issue&Volume: 2024-12-04

Abstract: The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development1,2,3. Although numerous cell-intrinsic mechanisms have been revealed4,5,6,7, 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.

DOI: 10.1038/s41586-024-08307-x

Source: https://www.nature.com/articles/s41586-024-08307-x