Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

中文翻译：

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纤维蛋白原抑制声波刺猬信号传导并损害血脑屏障破坏后的新生儿小脑发育


患有中枢神经系统（CNS）出血的早产儿的小脑损伤会导致持久的神经功能缺损并增加自闭症的风险。血液诱导途径对小脑发育的影响在很大程度上仍不清楚，因此尚未开发出特定的治疗方法来抵消早产儿神经血管损伤后血液的有害影响。在这里，我们发现纤维蛋白原（一种凝血蛋白）在损害新生儿小脑发育中起着核心作用。早产儿的纵向 MRI 显示，小脑出血是与小脑生长不良相关的最关键因素。使用新生小脑损伤的炎症和出血小鼠模型，我们发现纤维蛋白原增加先天免疫激活并阻碍发育中小脑的神经发生。纤维蛋白原抑制声刺猬（SHH）信号传导，这是小脑颗粒神经元祖细胞（CGNP）的主要有丝分裂途径，并且足以破坏小脑生长。遗传性纤维蛋白原耗竭可减轻神经炎症，促进 CGNP 增殖，并在神经血管损伤后保留正常的小脑发育。我们的研究结果表明，纤维蛋白原改变了神经血管生态位中 SHH 信号的平衡，并可能作为减轻中枢神经系统出血后发育性脑损伤的治疗靶点。