Fibrinogen inhibits sonic hedgehog signaling and impairs neonatal cerebellar development after blood-brain barrier disruption

• 成果类型: Article
• 署名作者: Weaver, Olivia; Gano, Dawn; Zhou, Yungui; Kim, Hosung; Tognatta, Reshmi; Yan, Zhaoqi; Ryu, Jae Kyu; Brandt, Caroline; Basu, Trisha; Grana, Martin; Cabriga, Belinda; Alzamora, Maria del Pilar S.; Barkovich, A. James; Akassoglou, Katerina; Petersen, Mark A.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; The J David Gladstone Institutes; University of California System; University of California San Francisco; The J David Gladstone Institutes; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of Southern California; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10229
• DOI: 10.1073/pnas.2323050121
• 发表日期: 2024-07-30
• 关键词: heparin-binding domain; mediated proliferation; born preterm; GROWTH; remyelination; beta; neurogenesis; expression; infection; microglia

摘要

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.