Intrathecal injection of 3D-mesenchymal stem cells attenuates disseminated neuroinflammation and improves cognitive function in controlled cortical impact rats.

BACKGROUND: Persistent cognitive impairment following traumatic brain injury (TBI) represents a significant unmet clinical need. Neuroinflammation has been implicated as one of the pathological processes that may contribute to this outcome. Given the limitations of current therapies, this study explored the therapeutic potential of three-dimensional cultured mesenchymal stem cells (3D-MSCs) for TBI, with a focus on long-term cognitive outcome and their immunomodulatory properties. METHODS: A controlled cortical impact (CCI) model was established in male Sprague-Dawley rats. Twenty-four hours post-injury, rats received an intrathecal injection of 1x106 3D-MSCs or vehicle. Cell migration, apoptosis, lesion volume, sensorimotor and cognitive functions, and neuroinflammation were subsequently evaluated. RESULTS: Intrathecally administered 3D-MSCs exhibited significant homing to the perilesional region within 24 h. Subsequently, the treatment reduced perilesional apoptosis by 59.0% at 48 h and lesion volume by 28.8% at 7 days post-injury (dpi). 3D-MSCs significantly enhanced sensorimotor recovery from day 3 and improved spatial learning and memory at 30 dpi. Importantly, it also attenuated CCI-induced widespread Iba1-associated neuroinflammatory responses across multiple brain regions at 7 dpi. CONCLUSION: Focal TBI can induce disseminated neuroinflammation. A single intrathecal injection of 3D-MSCs within 24 h after TBI enables rapid migration to the injury site and exerts early neuroprotective effects. In addition, 3D-MSC administration improved long-term cognitive function and attenuated disseminated neuroinflammatory responses, suggesting that immunomodulation may be one of the factors contributing to its therapeutic benefit.