Heterogeneous fibroblasts contribute to fibrotic scar formation after spinal cord injury in mice and monkeys

Xiaoyu Xue, Xianming Wu, Yongheng Fan, Shuyu Han, Haipeng Zhang, Yuting Sun, Yanyun Yin, Man Yin, Bing Chen, Zheng Sun, Shuaijing Zhao, Qi Zhang, Weiyuan Liu, Jiaojiao Zhang, Jiayin Li, Ya Shi, Zhifeng Xiao (), Jianwu Dai () and Yannan Zhao ()
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Xiaoyu Xue: Chinese Academy of Sciences
Xianming Wu: Chinese Academy of Sciences
Yongheng Fan: Chinese Academy of Sciences
Shuyu Han: Chinese Academy of Sciences
Haipeng Zhang: Chinese Academy of Sciences
Yuting Sun: Chinese Academy of Sciences
Yanyun Yin: Chinese Academy of Sciences
Man Yin: Chinese Academy of Sciences
Bing Chen: Chinese Academy of Sciences
Zheng Sun: Chinese Academy of Sciences
Shuaijing Zhao: Chinese Academy of Sciences
Qi Zhang: Chinese Academy of Sciences
Weiyuan Liu: Chinese Academy of Sciences
Jiaojiao Zhang: Chinese Academy of Sciences
Jiayin Li: Chinese Academy of Sciences
Ya Shi: Chinese Academy of Sciences
Zhifeng Xiao: Chinese Academy of Sciences
Jianwu Dai: Chinese Academy of Sciences
Yannan Zhao: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Spinal cord injury (SCI) leads to fibrotic scar formation at the lesion site, yet the heterogeneity of fibrotic scar remains elusive. Here we show the heterogeneity in distribution, origin, and function of fibroblasts within fibrotic scars after SCI in mice and female monkeys. Utilizing lineage tracing and single-cell RNA sequencing (scRNA-seq), we found that perivascular fibroblasts (PFs), and meningeal fibroblasts (MFs), rather than pericytes/vascular smooth cells (vSMCs), primarily contribute to fibrotic scar in both transection and crush SCI. Crabp2 + /Emb+ fibroblasts (CE-F) derived from meninges primarily localize in the central region of fibrotic scars, demonstrating enhanced cholesterol synthesis and secretion of type I collagen and fibronectin. In contrast, perivascular/pial Lama1 + /Lama2+ fibroblasts (LA-F) are predominantly found at the periphery of the lesion, expressing laminin and type IV collagen and functionally involved in angiogenesis and lipid transport. These findings may provide a comprehensive understanding for remodeling heterogeneous fibrotic scars after SCI.

Date: 2024
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DOI: 10.1038/s41467-024-50564-x

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