Dual strategies for neural injury repair: Targeted modulation of reactive astrocytes and functional astrocyte transplantation

Reactive astrogliosis-the adaptive structural and functional remodeling responses of astrocytes-is a biphasic response to neural injury. While initially protective, it often transitions into a chronic, detrimental state characterized by sustained neuroinflammation, blood-brain barrier disruption, and excitotoxicity, which collectively impede recovery. To address this, this review systematically compares the responses of reactive astrocytes across three major neural pathologies-traumatic brain injury, ischemic stroke, and spinal cord injury-identifying both conserved molecular targets that are shared across injuries and stage-specific targets that are unique to distinct phases of injury. Moreover, this review proposes a dual-intervention paradigm that integrates timely pharmacological inhibition of detrimental reactive astrocyte activity with the transplantation of functional astrocytes, with the goal of restoring tissue homeostasis. Key issues elaborated upon include the profound heterogeneity of astrocyte responses, which complicates targeted therapy, and the translational barriers associated with cell transplantation. This review advocates for interventions focused on the regulation of astrocyte functions to adopt a dual intervention paradigm: specifically, timely pharmacological intervention to inhibit the abnormal activity of harmful reactive astrocytes, combined with the transplantation of functional astrocytes to replenish the beneficial cell populations needed for repair. The synergy of these two approaches aims to restore homeostasis in the tissue microenvironment. However, this requires further clarification of the phenotype transitions of reactive astrocytes at different pathological stages, as well as optimizing the timing of interventions and the efficiency of drug delivery to ensure the specificity and safety of the treatment, which is crucial for enhancing the effectiveness of the intervention.