Dynamic Tuning of MSC-Based Scaffolds for Neurological Protection After Brain or CNS Injury

Neurological disorders, including stroke, traumatic brain injury, and spinal cord injury, constitute one of the most important causes of mortality and morbidity worldwide for which current treatment options focus on resolving neuroinflammation rather than on tissue and neuronal regeneration. Mesenchymal stem cells (MSCs) could be a potential therapeutic option due to their immunomodulatory, neuroprotective, and paracrine secretion of extracellular vesicles and trophic factors which modulate microglial activation, preserve blood-brain barrier (BBB) integrity, and neuroplasticity, but with limitations due by poor survival, retention, and phenotypic instability following direct transplantation. The purpose of this narrative review is to present mechanotransduction signaling pathways (integrin-FAK, PI3K/Akt, Rho/ROCK, and YAP/TAZ) through which MSC-based biomaterial scaffolds, especialy hyaluronic acid (HA) hydrogels, make the transition from reparative to regenerative medicine in central nervous system (CNS) injury. Even if most of the evidence from preclinical studies suggests that dynamically tunable MSC-scaffold systems represent promising platforms for neural tissue engineering and regenerative medicine, further translational studies and well-designed clinical investigations are required to establish their therapeutic efficacy and clinical applicability.