IL-4-primed human umbilical cord mesenchymal stem cells-derived extracellular vesicles facilitate recovery in spinal cord injury via the miR-21-5p/PDCD4-mediated shifting of macrophage M1/M2 polarization

Spinal cord injury (SCI) represents a significant neurological disorder that profoundly impacts human life. Transplantation of extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) has emerged as a promising therapeutic strategy. microRNA (miRNA) containing EVs serve as crucial mediators of intercellular communication, playing vital roles in physiological and pathological processes. Research indicates that EVs from hUC-MSCs could attenuate inflammation and facilitate recovery from SCI. Nevertheless, their application in clinical treatment necessitates further investigation. We are actively pursuing an effective approach to modulate the intensity of the inflammatory response, thereby addressing secondary SCI. Initially, we activated hUC-MSCs with interleukin-4 (IL-4) and subsequently harvested their EVs. We investigated the influences of A-hUC-MSCs-EVs compared to routinely acquired EVs on macrophage polarization phenotypes both in vitro and in vivo. Our results show that EVs originating from A-hUC-MSCs are more effective at promoting macrophage polarization from the M1 phenotype to the M2 phenotype than those derived from hUC-MSCs. Notably, we found that A-hUC-MSCs-derived EVs had a superior impact on motor function recovery in mice with SCI. Importantly, we observed that IL-4 activation significantly upregulated the expression of miR-21-5p within these EVs. More specifically, our data demonstrate that A-hUC-MSCs-EVs depend on miR-21-5p to inhibit the effects of PDCD4 on macrophage polarization. This mechanism regulates inflammatory responses while simultaneously reducing apoptosis. In summary, EVs derived from IL-4 primed hUC-MSCs are enriched with miR-21-5p, which exerts a pivotal influence in shifting macrophage polarization, alleviating inflammatory responses following SCI, and facilitating recovery.