Kdm6a-CNN1 axis orchestrates epigenetic control of trauma-induced spinal cord microvascular endothelial cell senescence to balance neuroinflammation for improved neurological repair

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Chengjun Li, Tian Qin, Jinyun Zhao, Yuxin Jin, Yiming Qin, Rundong He, Tianding Wu, Chunyue Duan, Liyuan Jiang, Feifei Yuan, Hongbin Lu, Yong Cao, Jianzhong Hu
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Abstract

Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors. Despite extensive investigations into vascular senescence associated with aging and degenerative diseases, the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress, particularly its involvement in senescence-induced inflammation, remain insufficiently elucidated. In this study, we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury (SCI). Lysine demethylase 6A (Kdm6a), commonly known as UTX, emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells (SCMECs). Upregulation of UTX induces senescence in SCMECs, leading to an amplified release of proinflammatory factors, specifically the senescence-associated secretory phenotype (SASP) components, thereby modulating the inflammatory microenvironment. Conversely, the deletion of UTX in endothelial cells shields SCMECs against senescence, mitigates the release of proinflammatory SASP factors, and promotes neurological functional recovery after SCI. UTX forms an epigenetic regulatory axis by binding to calponin 1 (CNN1), orchestrating trauma-induced SCMECs senescence and SASP secretion, thereby influencing neuroinflammation and neurological functional repair. Furthermore, local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion, reinstating a local regenerative microenvironment and enhancing functional repair after SCI. In conclusion, targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion, alleviate neuroinflammation, and provide a novel treatment strategy for SCI repair.

Abstract Image

Kdm6a-CNN1 轴协调创伤诱导的脊髓微血管内皮细胞衰老的表观遗传学控制,以平衡神经炎症,改善神经系统修复
细胞衰老通过分泌促炎因子在各种疾病中扮演着关键角色。尽管对与衰老和退行性疾病相关的血管衰老进行了广泛研究,但创伤应激诱导的微血管内皮细胞衰老的分子机制,尤其是其参与衰老诱导的炎症的机制,仍未得到充分阐明。在本研究中,我们对脊髓损伤(SCI)诱导的微血管内皮细胞衰老进行了全面的展示和表征。赖氨酸去甲基化酶 6A(Kdm6a),俗称UTX,是损伤脊髓微血管内皮细胞(SCMECs)细胞衰老的关键调控因子。UTX的上调会诱导脊髓微血管内皮细胞衰老,导致促炎因子,特别是衰老相关分泌表型(SASP)成分的释放增加,从而调节炎症微环境。相反,内皮细胞中UTX的缺失可保护SCMECs免受衰老的影响,减轻促炎SASP因子的释放,促进损伤后神经功能的恢复。UTX通过与钙蛋白1(CNN1)结合形成表观遗传调控轴,协调创伤诱导的SCMECs衰老和SASP分泌,从而影响神经炎症和神经功能修复。此外,在局部注射溶解衰老的药物可减少衰老的 SCMECs 并抑制促炎性 SASP 的分泌,从而恢复局部再生微环境并加强 SCI 后的功能修复。总之,针对UTX-CNN1表观遗传轴防止创伤诱导的SCMECs衰老有望抑制SASP分泌,减轻神经炎症,为SCI修复提供一种新的治疗策略。
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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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