2. Academic Validation
  3. 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

  • Glia. 2023 Aug;71(8):1985-2004. doi: 10.1002/glia.24378.
Aimei Liu 1 2,  Lingtai Yu 1,  Xuejun Li 1,  Kejiao Zhang 1,  Wei Zhang 1,  Kwok-Fai So 1 2 3 4 5,  Fadel Tissir 6 7,  Yibo Qu 1 4 5,  Libing Zhou 1 2 3 4 5
Affiliations

Affiliations

  • 1 Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University)-Ministry of Education, Guangzhou, People's Republic of China.
  • 2 Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, Shandong, People's Republic of China.
  • 3 Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou, People's Republic of China.
  • 4 Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, People's Republic of China.
  • 5 Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, People's Republic of China.
  • 6 Institute of Neuroscience, Developmental Neurobiology, Université catholique de Louvain, Brussels, Belgium.
  • 7 College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Doha, Qatar.
PMID: 37186402 DOI: 10.1002/glia.24378
Abstract

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 of Celsr2 results 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 of Celsr2 enhances calcium influx in reactive astrocytes in time-lapse imaging. Morphological phenotypes of cultured Celsr2-/- 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 of Celsr2 in astrocytes. In Celsr2-/- 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 in Celsr2-/- mice with SCI. In conclusion, Celsr2 regulates morphological polarization and functional phenotype of reactive astrocytes and inactivating Celsr2 is a potential therapeutic strategy for neural repair.

Keywords

astrocyte phenotypes; astrocyte polarization; atypical cadherins; calcium; neural repair; small GTPase; spinal cord injury.

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