Meng Han, Zhao Youyi, Li Yuqian, Fan Hong, Yi Xuyang, Meng Xinyu, Wang Pengfei, Fu Fanfan, Wu Shengxi, Wang Yazhou
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research, Center for Dental Materials and Advanced Manufacture, Department of Anethesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
Front Cell Dev Biol. 2023 Jul 27;11:1229788. doi: 10.3389/fcell.2023.1229788. eCollection 2023.
During development, apoptosis removes redundant cells and ensures proper organ morphogenesis. Necrosis is long known as an adult-bound inflammatory and pathologic cell death. Whether there exists physiological necrosis during early development has been speculated but yet clearly demonstrated. Here, we report evidence of necroptosis, a type of programmed necrosis, specifically in perivascular cells of cerebral cortex and skin at the early stage of development. Phosphorylated Mixed Lineage Kinase Domain-Like protein (MLKL), a key molecule in executing necroptosis, co-expressed with blood endothelial marker CD31 and venous-lymphatic progenitor marker Sox18. Depletion of did not affect the formation of blood vessel network but increased the differentiation of venous-lymphatic lineage cells in postnatal cerebral cortex and skin. Consistently, significant enhancement of cerebrospinal fluid diffusion and lymphatic drainage was found in brain and skin of -deficient mice. Under hypobaric hypoxia induced cerebral edema and inflammation induced skin edema, mutation significantly attenuated brain-blood-barrier damage and edema formation. Our data, for the first time, demonstrated the presence of physiological vascular-associated necroptosis and its potential involvement in the development of venous-lymphatic vessels.
在发育过程中，细胞凋亡可清除多余细胞并确保器官正常形态发生。坏死长期以来被认为是一种与成人相关的炎症性和病理性细胞死亡。早期发育过程中是否存在生理性坏死一直存在推测，但尚未得到明确证实。在此，我们报告了程序性坏死（一种程序性坏死类型）的证据，具体发生在发育早期大脑皮层和皮肤的血管周围细胞中。磷酸化混合谱系激酶结构域样蛋白（MLKL）是执行程序性坏死的关键分子，与血管内皮标志物CD31和静脉-淋巴管祖细胞标志物Sox18共同表达。基因敲除并不影响血管网络的形成，但增加了出生后大脑皮层和皮肤中静脉-淋巴谱系细胞的分化。一致地，在基因敲除小鼠的大脑和皮肤中发现脑脊液扩散和淋巴引流显著增强。在低压缺氧诱导的脑水肿和炎症诱导的皮肤水肿中，基因突变显著减轻了血脑屏障损伤和水肿形成。我们的数据首次证明了生理性血管相关程序性坏死的存在及其在静脉-淋巴管发育中的潜在作用。
