引言
器官纤维化是多种疾病的主要病理学特征,而全球疾病死因约有三分之一归于纤维化【1】。肺纤维化导致患者呼吸衰竭和死亡,平均生存周期低于肺癌。现有药物无法有效逆转纤维化进程。促进纤维化肺组织再生可望恢复受损的肺泡和血管结构,为包括肺纤维化在内的多种疾病治疗提供策略。因此发掘肺修复中促再生并抑制纤维化治疗靶点具有临床价值。
丁楅森和曹中炜以往工作发现血管内皮细胞通过旁分泌“Angiocrine”因子与邻近的上皮、间质及血液细胞互作从而调控肺的再生和纤维化【2-8】。2024年8月6日,四川大学丁楅森/曹中炜团队和华西医院叶庭洪、蒲强、张鸣及哈医大杨力明合作在Cell Metabolism 杂志发表题为Dopaminylation of endothelial TPI1 suppresses ferroptotic angiocrine signals to promote lung regeneration over fibrosis 的研究论文,通过整合点击化学、蛋白组学、基因敲除/敲入鼠、临床分析等多学科手段,发现多巴胺通过修饰肺血管triosephosphate isomerase 1 (TPI1) 调控Angiocrine因子,抑制铁死亡从而促进肺再生并抑制纤维化。


模式图(Credit: Cell Metabolism)
总之,该研究发现了肺血管微环境靶点TPI1的多巴胺化修饰抑制铁死亡,从而维持促再生的angiocrine功能,并抑制肺纤维化。所揭示的Angiocrine调控机制可为器官纤维化的再生疗法提供靶点,开发靶向血管微环境药物。参考文献
1. Rockey DC, Bell PD, Hill JA: Fibrosis--a common pathway to organ injury and failure. The New England journal of medicine 2015, 372:1138-49.2. Rafii, S., Butler, J. M., and Ding, B. S. (2016) Angiocrine functions of organ-specific endothelial cells. Nature 529, 316-3252.3. Cao, Z., Lis, R., Ginsberg, M., Chavez, D., Shido, K., Rabbany, S. Y., Fong, G. H., Sakmar, T. P., Rafii, S., and Ding, B. S. (2016) Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis. Nature medicine 22, 154-1623.4. Rafii, S., Cao, Z., Lis, R., Siempos, II, Chavez, D., Shido, K., Rabbany, S. Y., and Ding, B. S. (2015) Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration. Nature Cell Biology 17, 123-1364.5. Ding, B. S., Cao, Z., Lis, R., Nolan, D. J., Guo, P., Simons, M., Penfold, M. E., Shido, K., Rabbany, S. Y., and Rafii, S. (2014) Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97-1025.6. Ding, B. S., Yang, D., Swendeman, S. L., Christoffersen, C., Nielsen, L. B., Friedman, S. L., and Cao, Z. (2020). Aging suppresses sphingosine-1-phosphate chaperone ApoM in circulation resulting in maladaptive organ repair. Developmental cell, 53(6), 677-690.7. Chen, Y., Pu, Q., Ma, Y., Zhang, H., Ye, T., Zhao, C., Huang, X., Ren, Y., Qiao, L., Liu, H. M., Esmon, C. T., Ding, B. S., and Cao, Z. (2021) Aging Reprograms the Hematopoietic-Vascular Niche to Impede Regeneration and Promote Fibrosis. Cell Metabolism 33, 395-410 e3948. Zhang, H., Ma, Y., Cheng, X., Wu, D., Huang, X., Chen, B., and Cao, Z. (2021). Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis. Science translational medicine, 13(614), eabd1206.https://doi.org/10.1016/j.cmet.2024.07.008责编|探索君
排版|探索君
文章来源|“BioArt”
End
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