Maternal IL-10 restricts fetal emergency myelopoiesis [scATAC-seq]. Maternal IL-10 restricts fetal emergency myelopoiesis [scATAC-seq]

We investigated how late fetal liver (FL) mouse hematopoieitic stem and progenitor cells (HSPC) respond to inflammation, with the hypothesis that deficits in engagement of emergency myelopoiesis (EM) pathways could limit neutrophil output and contribute to perinatal neutropenia, ultimately explaining the susceptibility of neonates to inflammation and infection. We show that fetal HSPCs are biased toward erythroid and lymphoid cell production at steady state and fail to mount classical EM responses in vivo. Despite being capable of responding to EM-inducing stimuli in vitro, we find that maternal factors like interleukin-10 (IL-10) restrict fetal HSPCs from activating EM pathways in utero. Accordingly, we find that loss of maternal IL-10 restores EM activation in fetal HSPCs but at a cost of premature parturition. These results reveal the evolutionary trade-off inherent in maternal anti-inflammatory responses that maintain pregnancy but render the fetus susceptible to infection. Overall design: We sorted lineage negative, c-Kit positive cells from fetal liver of embryonic day 18.5 (E18.5) mice and bone marrow of adult mice.本研究旨在探究小鼠晚期胎肝（fetal liver, FL）中的造血干祖细胞（hematopoietic stem and progenitor cells, HSPC）对炎症的响应机制，核心假说为：紧急髓系造血（emergency myelopoiesis, EM）通路激活不足会限制中性粒细胞生成，进而引发围产期中性粒细胞减少症，最终解释新生儿对炎症与感染的易感性。研究发现，稳态条件下胎肝造血干祖细胞偏向于生成红系与淋巴系细胞，且无法在体内触发典型的紧急髓系造血应答。尽管胎肝造血干祖细胞在体外可响应紧急髓系造血诱导刺激，但我们观察到，母体来源的白细胞介素10（interleukin-10, IL-10）等因子会在子宫内抑制其激活紧急髓系造血通路。进一步实验证实，敲除母体的IL-10可恢复胎肝造血干祖细胞的紧急髓系造血激活能力，但会以早产为代价。上述结果揭示了母体抗炎应答固有的进化权衡：这类应答虽能维持妊娠，却会使胎儿更易发生感染。实验整体设计：我们分别从胚胎第18.5天（E18.5）小鼠的胎肝以及成年小鼠骨髓中，分选得到谱系阴性、c-Kit阳性的细胞群。