动态的成纤维细胞 - 免疫相互作用塑造脑损伤后的恢复过程。

Dynamic fibroblast-immune interactions shape recovery after brain injury.

作者信息

Ewing-Crystal Nathan A, Mroz Nicholas M, Larpthaveesarp Amara, Lizama Carlos O, Pennington Remy, Chiaranunt Pailin, Dennis Jason I, Chang Anthony A, Merrill Eric Dean, Caryotakis Sofia E, Kirthivasan Nikhita, Teo Leon, Tsukui Tatsuya, Katewa Aditya, McKinsey Gabriel L, Nelson Sophia C K, Ciesielska Agnieszka, Lummis Nicole C, Pintarić Lucija, Dahlgren Madelene W, Atakilit Amha, Paidassi Helena, Jain Saket, Liu Xiaodan, Xu Duan, Aghi Manish K, Bourne James A, Paz Jeanne T, Daneman Richard, Gonzalez Fernando F, Sheppard Dean, Molofsky Anna V, Arnold Thomas D, Molofsky Ari B

机构信息

Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.

Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.

出版信息

Nature. 2025 Sep 3. doi: 10.1038/s41586-025-09449-2.

DOI:10.1038/s41586-025-09449-2

PMID:40903576

Abstract

Fibroblasts and immune cells coordinate tissue regeneration and necessary scarring after injury. In the brain, fibroblasts are border-enriched cells whose dynamic molecular states and immune interactions after injury remain unclear. Here we define the shared fibroblast-immune response to brain injury. Early profibrotic myofibroblasts develop from pre-existing brain fibroblasts and infiltrate brain lesions, orchestrated by fibroblast TGFβ signalling, profibrotic macrophages and microglia, and perilesional glia. Myofibroblasts transition into several late fibroblast states, including lymphocyte-interactive fibroblasts. Interruption of the early myofibroblast state exacerbated sub-acute brain injury, tissue loss and secondary neuroinflammation, with increased mortality in the transient middle cerebral artery occlusion stroke model. Disruption of late lymphocyte-fibroblast niches via selective loss of fibroblast chemokine CXCL12 led to late brain-specific innate inflammation and lymphocyte dispersal with increased IFNγ production. These data indicate the response to brain injury is coordinated by evolving temporal and spatial fibroblast states that limit functional tissue loss and chronic neuroinflammation.

摘要

成纤维细胞和免疫细胞在损伤后协调组织再生和必要的瘢痕形成。在大脑中，成纤维细胞是边界富集细胞，其损伤后的动态分子状态和免疫相互作用尚不清楚。在此，我们定义了对脑损伤的成纤维细胞-免疫共同反应。早期促纤维化肌成纤维细胞由预先存在的脑成纤维细胞发育而来，并浸润脑损伤部位，这一过程由成纤维细胞转化生长因子β信号传导、促纤维化巨噬细胞和小胶质细胞以及损伤周围神经胶质细胞协调完成。肌成纤维细胞转变为几种晚期成纤维细胞状态，包括淋巴细胞相互作用的成纤维细胞。在短暂性大脑中动脉闭塞性中风模型中，早期肌成纤维细胞状态的中断加剧了亚急性脑损伤、组织损失和继发性神经炎症，死亡率增加。通过选择性缺失成纤维细胞趋化因子CXCL12破坏晚期淋巴细胞-成纤维细胞微环境，导致晚期脑特异性先天性炎症和淋巴细胞扩散，同时干扰素γ产生增加。这些数据表明，对脑损伤的反应是由不断演变的时空成纤维细胞状态协调的，这些状态限制了功能性组织损失和慢性神经炎症。