Interorgan communication in neurogenic heterotopic ossification: the role of brain-derived extracellular vesicles.

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-02-22 DOI:10.1038/s41413-023-00310-8
Weicheng Lu, Jianfei Yan, Chenyu Wang, Wenpin Qin, Xiaoxiao Han, Zixuan Qin, Yu Wei, Haoqing Xu, Jialu Gao, Changhe Gao, Tao Ye, Franklin R Tay, Lina Niu, Kai Jiao
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Abstract

Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury. Inflammasome-related proteins encapsulated in brain-derived extracellular vesicles can cross the blood‒brain barrier to reach distal tissues. These proteins initiate inflammatory dysfunction, such as neurogenic heterotopic ossification. This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies. Accordingly, a rat model of neurogenic heterotopic ossification induced by combined traumatic brain injury and achillotenotomy was developed to address these two issues. Histological examination of the injured tendon revealed the coexistence of ectopic calcification and fibroblast pyroptosis. The relationships among brain-derived extracellular vesicles, fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo. The present work highlights the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offers a potential strategy for preventing neurogenic heterotopic ossification after traumatic brain injury. Brain-derived extracellular vesicles (BEVs) are released after traumatic brain injury. These BEVs contain pathogens and participate in interorgan communication to initiate secondary injury in distal tissues. After achillotenotomy, the phagocytosis of BEVs by fibroblasts induces pyroptosis, which is a highly inflammatory form of lytic programmed cell death, in the injured tendon. Fibroblast pyroptosis leads to an increase in calcium and phosphorus concentrations and creates a microenvironment that promotes osteogenesis. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk suppressed fibroblast pyroptosis and effectively prevented the onset of heterotopic ossification after neuronal injury. The use of a pyroptosis inhibitor represents a potential strategy for the treatment of neurogenic heterotopic ossification.

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神经源性异位骨化中的器官间通信:脑源性细胞外囊泡的作用。
脑源性细胞外囊泡参与脑外伤后的器官间交流,运输病原体以引发二次损伤。包裹在脑源性细胞外囊泡中的炎症相关蛋白可穿过血脑屏障到达远端组织。这些蛋白质会引发炎症功能障碍,如神经源性异位骨化。由于发病机制相对不明,且缺乏有效的预防性干预策略,这种反复发作的病症对患者造成了极大的伤害。因此,为了解决这两个问题,我们建立了一个由脑外伤和腱鞘切除术联合诱发神经源性异位骨化的大鼠模型。损伤肌腱的组织学检查显示,异位钙化和成纤维细胞热解同时存在。研究人员在体外和体内进一步研究了脑源性细胞外囊泡、成纤维细胞热解和异位钙化之间的关系。静脉注射热凋亡抑制剂 Ac-YVAD-cmk 逆转了体内神经源性异位骨化的发展。本研究强调了脑源性细胞外囊泡在神经源性异位骨化发病机制中的作用,并为预防脑外伤后神经源性异位骨化提供了一种潜在的策略。脑外伤后会释放脑源性细胞外囊泡(BEVs)。这些脑源性细胞外囊泡含有病原体,并参与器官间的交流,从而引发远端组织的继发性损伤。肌腱腱鞘切除术后,成纤维细胞对 BEVs 的吞噬会诱发受伤肌腱的热凋亡,这是一种高度炎症性的溶解性程序性细胞死亡。成纤维细胞的热解导致钙和磷浓度增加,并创造了一种促进成骨的微环境。静脉注射成纤维细胞增殖抑制剂 Ac-YVAD-cmk 可抑制成纤维细胞增殖,有效防止神经元损伤后异位骨化的发生。使用热蛋白沉积抑制剂是治疗神经源性异位骨化的一种潜在策略。
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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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