We earlier showed that outside-in integrin signaling through POSTN-ITGAV interaction plays an important role in regulating adult hematopoietic stem cell (HSC) quiescence. Here, we show that Itgav deletion results in increased frequency of phenotypic HSCs in fetal liver (FL) due to faster proliferation. Systemic deletion of Postn led to increased proliferation of FL HSCs, albeit without any loss of stemness, unlike Vav-Itgav^−/− HSCs. Based on RNA sequencing analysis of FL and bone marrow HSCs, we predicted the involvement of DNA damage response pathways in this dichotomy. Indeed, proliferative HSCs from Postn-deficient FL tissues showed increased levels of DNA repair, resulting in lesser double-strand breaks. Thus POSTN, with its expression majorly localized in the vascular endothelium of FL tissue, acts as a regulator of stem cell pool size during development. Overall, we demonstrate that the duality of response to proliferation in HSCs is developmental stage dependent and can be correlated with DNA damage responses.

我们早些时候表明，通过 POSTN-ITGAV 相互作用的外在整合素信号传导在调节成体造血干细胞 (HSC) 静止中起重要作用。在这里，我们表明由于更快的增殖， Itgav缺失导致胎儿肝脏 (FL) 中表型 HSC 的频率增加。与Vav-Itgav ^-/- HSCs不同， Postn的系统性缺失导致 FL HSCs 的增殖增加，尽管没有任何干性损失。基于 FL 和骨髓 HSCs 的 RNA 测序分析，我们预测了 DNA 损伤反应途径参与这种二分法。事实上，来自Postn的增殖性 HSC- 缺乏 FL 组织的 DNA 修复水平增加，导致双链断裂较少。因此，POSTN，其表达主要定位于 FL 组织的血管内皮，在发育过程中充当干细胞池大小的调节剂。总体而言，我们证明了对 HSC 增殖反应的二元性依赖于发育阶段，并且可能与 DNA 损伤反应相关。