Genetic Modification of Mesenchymal Stem Cell to Overexpress CXCR4 Enhances Treatment Efficacy for Brain Injury After Cardiopulmonary Resuscitation

ABSTRACT Aim To investigate whether genetically modifying human umbilical cord‐derived mesenchymal stem cells (MSC) to overexpress the CXCR4 receptor can enhance their therapeutic efficacy for treating brain injury following cardiac arrest (CA). Methods MSC were engineered to overexpress CXCR4 (CXCR4‐MSC) via lentiviral transduction. The migration capacity of these cells was tested using in vitro chemotaxis assays. In a rat model of CA/CPR, the homing ability of CXCR4‐MSC to the brain was tracked in vivo, and their therapeutic effects on neuronal death and neurological recovery were assessed. The role of exosomes and their impact on key proteins (NLRP3, ASC, GSDMD) in the pyroptosis pathway was also investigated. Result CXCR4 overexpression significantly enhanced the migration of MSC in vitro and their homing to injured brain tissue in vivo. Treatment with CXCR4‐MSC markedly reduced neuronal death and improved neurological recovery in resuscitated rats. This was accompanied by decreased expression of NLRP3. Furthermore, exosomes derived from CXCR4‐MSC were found to suppress pyroptosis‐related proteins (NLRP3/ASC/GSDMD) in post‐CPR neurons, an effect that was reversed upon exosome inhibition. Conclusion Genetic modification to overexpress CXCR4 enhances the therapeutic efficacy of MSC for CA‐induced brain injury by promoting their migration to the brain via the CXCL12/CXCR4 axis. A key mechanism of this protection is exosome‐mediated inhibition of neuronal pyroptosis.