The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development^1,2,3. Although numerous cell-intrinsic mechanisms have been revealed^4,5,6,7, 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.

在胚胎发育过程中，维持快速增殖细胞的基因组完整性是一项重大挑战^1,2,3。尽管已经揭示了许多细胞内在机制^{4,5,6,7，但}对基因组保护作用和发育组织微环境对组织形成细胞的影响知之甚少。在这里，我们表明胎儿肝细胞为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竭表明，早期胎儿肝脏中肝细胞发育延迟增加了新定植 HSPC 的染色体不稳定性。此外，HSPCs 对肝细胞条件培养基中的基因毒素产生了耐受性，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，胎球蛋白-A 在肝细胞条件培养基中富集，但在早期胎儿肝脏中未富集。胎球蛋白-A 激活 Toll 样受体通路，以防止在胎儿肝脏中经历 DNA 复制和基因转录的 HSPC 中致病性 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 环富集区域有关。在 Fetua 敲除小鼠中，HSPCs 表现出基因组不稳定性增加和对恶性肿瘤诱导的易感性。此外，低浓度的胎球蛋白-A 与儿童白血病的肿瘤发生相关。因此，我们揭示了一种在发育组织中起作用的机制，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。