How do CNS fibroblasts regulate the response to neuroinflammation?

摘要 纤维化，定义为I型胶原沉积，是一种破坏性的病理事件，在许多情况下发生 包括心脏、肾脏、肝脏和肺在内的器官对损伤和炎症做出反应。这种纤维化反应 抑制炎症的恢复，甚至可能导致器官衰竭。尽管潜在的重要性，但很少是 已知在以下情况下中枢神经系统(CNS)是否有纤维化反应 在多发性硬化症、视神经脊髓炎、中风和中枢神经系统等疾病中发生的神经炎症 感染，以及这种反应如何影响修复和恢复。使用实验性自身免疫 脑脊髓炎(EAE)，一种神经炎症的小鼠模型，我们已经发现一种强大的胶原蛋白I- 基底性纤维性瘢痕形成覆盖神经炎性病变，我们假设这个纤维性瘢痕 抑制修复细胞进入病变的能力。在初步研究中使用了血统追踪和单一 细胞测序，我们已经确定这一纤维化瘢痕是由活化和增殖形成的 成纤维细胞。我们进一步建立了分离和培养CNS成纤维细胞的方法，提供了一种体外 模型来研究这些细胞的增殖、迁移和产生1型胶原的情况。在这项提案中，我们的目标是 以确定纤维性瘢痕对神经炎症后的康复是有帮助还是有害，并 进一步研究纤维性瘢痕形成的调控机制。我们将首先确定是否抑制 纤维性瘢痕的形成可以增加EAE的恢复。然后我们将研究转化生长因子β和 PDGFR信号通路调控纤维性瘢痕的形成。我们假设转化生长因子β信号驱动 成纤维细胞的增殖和I型胶原的产生以及PDGFR信号调节细胞迁移 成纤维细胞对病变的影响。我们的目标是确定调控纤维性瘢痕是否有潜力 帮助神经炎症性疾病患者康复的治疗目标。

ABSTRACT Fibrosis, defined by the deposition of collagen I, is a devastating pathological event that occurs in many organs including the heart, kidney, liver and lung in response to injury and inflammation. This fibrotic response inhibits recovery inflammation and can even lead to organ failure. Despite the potential importance, very little is known about whether there is a fibrotic response in the central nervous system (CNS) following neuroinflammation that occurs in diseases such as multiple sclerosis, neuromyelitis optica, stroke and CNS infections, and how this response affects repair and recovery. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation, we have identified that a robust collagen I- based fibrotic scar forms covering the neuroinflammatory lesion and we hypothesize that this fibrotic scar inhibits the ability of reparative cells to enter the lesion. In preliminary studies using lineage tracing and single cell sequencing, we have identified that this fibrotic scar is formed by the activation and proliferation of fibroblasts. We have further generated methods to isolate and culture CNS fibroblasts providing an in vitro model to study the proliferation, migration and collagen 1 production from these cells. In this proposal we aim to determine whether the fibrotic scar is helpful or harmful for recovery following neuroinflammation and to further study the mechanisms that regulate fibrotic scar formation. We will first determine whether inhibition of fibrotic scar formation can lead to an increased recovery from EAE. We will then examine whether TGFβ and PDGFR signaling pathways regulate fibrotic scar formation. We hypothesize that TGFβ signaling drives the proliferation and collagen I production by the fibroblasts and that PDGFR signaling regulates the migration of the fibroblasts to the lesion. Our goal is to determine whether modulating the fibrotic scar is a potential therapeutic target to aid in recovery for patients with neuroinflammatory diseases.