Rictor/mTORC2 signaling pathway protects endogenous neural stem cells to promote recovery after spinal cord injury.

Although endogenous neural stem cells represent a promising target for noninvasive spinal cord injury repair, inflammatory lesion environments frequently trigger their death. Our prior work identified necroptosis as a key death pathway for endogenous neural stem cells migrating to spinal cord injury lesions. Rapamycin-insensitive companion of mTOR (Rictor; a core component of the mechanistic target of rapamycin complex 2 [mTORC2] complex) regulates neural stem cell self-renewal and differentiation, and our preliminary data implicate it in spinal cord injury repair; however, its role in promoting endogenous neural stem cell survival post-spinal cord injury remains unclear. Here, we generated conditional endogenous neural stem cell-specific Rictor knockout mice using the Cre-loxP system. Although the endogenous neural stem cell-specific Rictor knockout mice displayed normal baseline spinal cord morphology and function, they exhibited impaired functional recovery after spinal cord injury compared with wild-type controls. This deficit correlated with elevated inflammatory responses and the increased susceptibility of endogenous neural stem cells to necroptosis. Mechanistically, lentiviral-mediated Rictor knockdown in neural stem cells in vitro impaired lysosomal function, leading to heightened sensitivity to tumor necrosis factor-alpha- and lipopolysaccharide-induced necroptosis. Collectively, these findings indicate that Rictor/mTORC2 signaling protects endogenous neural stem cells against receptor-interacting protein kinase 1-mediated necroptosis following spinal cord injury. Consequently, the modulation of intrinsic Rictor activity represents a potential therapeutic strategy to enhance endogenous neural stem cell survival and functional recovery post-spinal cord injury.