Celsr2-mediated morphological polarization and functional phenotype of reactive astrocytes in neural repair
Celsr2-mediated morphological polarization and functional phenotype of reactive astrocytes in neural repair
复制标题
DOI：
10.1002/glia.24378
复制
发表时间：
2023-04-26
期刊：
影响因子：
6.2
通讯作者：
Zhou，Libing
中科院分区：
文献类型：
--
作者：
Liu，Aimei;Yu，Lingtai;Zhou，Libing
神经修复受到反应性星形胶质细胞的高度影响。非典型钙粘蛋白Celsr 2调节神经元发育和轴突再生，而其在神经胶质细胞中的作用仍有待研究。在这项研究中，我们表明，Celsr 2是高度表达的成年小鼠脊髓星形胶质细胞，和敲除Celsr 2的结果在反应性星形胶质细胞与较长的突起优先定向向病变边界在文化划痕试验和损伤的脊髓，和总的和活性Cdc 42和Rac 1蛋白的蛋白质在蛋白质印迹的升高。失活Celsr 2增强反应性星形胶质细胞中的钙内流Cdc 42或Rac 1抑制剂可挽救Celsr 2 −/−星形胶质细胞的形态学表型。脊髓损伤（SCI）后，Celsr 2 −/−小鼠表现出较小的病变腔和胶质瘢痕，增强的纤维再生，较弱的小胶质细胞反应，并改善功能恢复比对照动物。在星形胶质细胞中条件性敲除Celsr 2的小鼠中发现了类似的表型。在Celsr 2 −/−小鼠中，星形胶质细胞表型发生变化，损伤后神经炎症减轻。抑制Cdc 42/Rac 1活性会损害星形胶质细胞极化，并改善SCI Celsr 2 −/−小鼠的神经修复和功能恢复。总之，Celsr 2调节反应性星形胶质细胞的形态极化和功能表型，失活Celsr 2是神经修复的潜在治疗策略。
Neural repair is highly influenced by reactive astrocytes. Atypical cadherin Celsr2 regulates neuron development and axon regeneration, while its role in glial cells remains unexplored. In this study, we show that Celsr2 is highly expressed in spinal astrocytes of adult mice, and knockout ofCelsr2results in reactive astrocytes with longer protrusions preferentially orientated towards lesion borders in culture scratch assay and injured spinal cord, and elevation of total and active Cdc42 and Rac1 protein in western blots. Inactivation ofCelsr2enhances calcium influx in reactive astrocytes in time‐lapse imaging. Morphological phenotypes of culturedCelsr2−/−astrocytes are rescued by Cdc42 or Rac1 inhibitors. Following spinal cord injury (SCI),Celsr2−/−mice exhibit smaller lesion cavity and glial scar, enhanced fiber regeneration, weaker microglial response, and improved functional recovery than control animals. Similar phenotypes are found in mice with conditional knockout ofCelsr2in astrocytes. InCelsr2−/−mice, astrocyte phenotype is changed and neuroinflammation is alleviated after injury. Inhibiting Cdc42/Rac1 activities compromises astrocyte polarization and the improvement of neural repair and functional recovery inCelsr2−/−mice with SCI. In conclusion, Celsr2 regulates morphological polarization and functional phenotype of reactive astrocytes and inactivatingCelsr2is a potential therapeutic strategy for neural repair.