Jones Hannah E, Abrams Kelsey A, Fantauzzo Katherine A, Siegenthaler Julie A
Department of Pediatrics, Section of Developmental Biology, Anschutz Medical Campus Aurora, CO, USA 80025.
Cell Biology, Stem Cells and Development Graduate Program, Anschutz Medical Campus Aurora, CO, USA 80025.
bioRxiv. 2025 Jun 7:2025.06.07.658411. doi: 10.1101/2025.06.07.658411.
Perivascular fibroblasts (PVFs) are a cell type associated with large diameter blood vessels in the brain and spinal cord parenchyma and leptomeninges. PVFs have previously defined roles in injury and neuroinflammatory diseases and predicted roles in supporting neurovascular function. The temporal dynamics of PVF development in the pre- and postnatal cerebral cortex have recently been described, however the molecular mechanisms that underly PVF development have not been identified. PVFs express both platelet derived growth factor receptors (PDGFRs), PDGFRα and PDGFRβ. Here we investigate the role of PDGF signaling in PVF development. We use immunohistochemistry and RNA transcript detection methods to show developmental expression of PDGFRs by PVFs and examine distribution of PDGF ligand expression in the brain. We show that postnatal deletion of PDGFRα in fibroblasts using the mouse line significantly impairs PVF coverage of cerebral vessels at postnatal day 10. Perivascular macrophages, a cell type previously shown to co-develop with PVFs, have impaired cerebral vessel coverage in conditional mutants that is similar to PVF coverage defects. This work establishes a requirement for PDGFRα signaling in PVF development and may shed light upon the potential pathways that are over-activated in PVFs in injury and disease contexts.
血管周围成纤维细胞(PVFs)是一种与脑实质、脊髓实质和软脑膜中的大直径血管相关的细胞类型。PVFs在损伤和神经炎症性疾病中具有先前已明确的作用,并在支持神经血管功能方面具有预测作用。最近已描述了出生前和出生后大脑皮质中PVF发育的时间动态,但尚未确定PVF发育的分子机制。PVFs表达血小板衍生生长因子受体(PDGFRs),即PDGFRα和PDGFRβ。在此,我们研究PDGF信号在PVF发育中的作用。我们使用免疫组织化学和RNA转录检测方法来显示PVFs对PDGFRs的发育性表达,并检查大脑中PDGF配体表达的分布。我们发现,使用小鼠品系在出生后成纤维细胞中敲除PDGFRα会显著损害出生后第10天脑血管的PVF覆盖。血管周围巨噬细胞是一种先前已证明与PVFs共同发育的细胞类型,在条件性突变体中其脑血管覆盖受损,这与PVF覆盖缺陷相似。这项工作确定了PVF发育中对PDGFRα信号的需求,并可能揭示在损伤和疾病情况下PVFs中过度激活的潜在途径。