Traumatic brain injury (TBI) is a leading cause of persistent cognitive, motor, and neuropsychiatric impairment, arising from both the initial mechanical insult and a prolonged cascade of secondary injury processes. While primary injury reflects structural damage, secondary mechanisms, including neuroinflammation, oxidative stress, apoptosis, and blood-brain barrier disruption, evolve over time and critically influence long-term outcomes. Despite extensive investigation, therapies targeting isolated components of secondary injury have demonstrated limited clinical success, highlighting the need for approaches that support coordinated neural repair. Stem cell-based therapies have emerged as a promising neurorestorative strategy. Rather than replacing lost neurons directly, transplanted cells primarily act through paracrine signaling, immunomodulation, neurotrophic support, and preservation of vulnerable neural networks. However, clinical translation has been constrained by heterogeneity in cell sources, delivery routes, treatment timing, and outcome measures, limiting mechanistic interpretability across trials. This review presents a mechanism-aligned translational framework linking injury stage, biological targets, route of administration, and clinically meaningful outcomes across stages of TBI. We integrate current knowledge of post-injury repair mechanisms with evidence from recent human clinical trials of stem cell therapies. Particular emphasis is placed on safety, feasibility, and emerging signals across structural and functional endpoints, as well as how injury stage, biological targets, delivery strategies, and meaningful endpoints interact to shape treatment responsiveness and inform biomarker-guided clinical trial design.
Creel et al. (Thu,) studied this question.