Therapeutic potential of macrophages in ischemic skeltal muscle repair

Peripheral arterial disease (PAD) affects more than 8 million patients in the US. The gradual obstruction of blood supply causes skeletal muscle to degenerate and regenerate. Among various cells mediating these processes, it has been indicated that macrophages (MPs) are important for efficient muscle repair. In this project, we characterized the temporal transition of monocyte/ MP phenotype in muscle following ischemia in response to regenerative events to decide the timing of treatment. Then we tested the effect of MPs-mediated cell therapy through adoptive transfer of MPs in ischemic muscle. Our data showed that transplantation of in vitro polarized pro-inflammatory M1 MPs on day 1 post-FAE generated the best results with increased myofiber size, perfusion, capillary density and muscle contractile force. On the other hand, delivery of anti-inflammatory M2 MPs on day 3 post-FAE showed improvement of muscle recovery. In order to eliminate the cytokine manipulation, we exploited the immunoregulatory property of ASCs and examined the effect of co-delivering ASCs and unpolarized M0 MPs on ischemic muscle regeneration. Co-injection of ASCs and M0 MPs resulted in greatly improved muscle morphology and function with enhanced tissue perfusion. These data demonstrated that intramuscular administration of MPs hastened the muscle regeneration and may serve as a promising therapeutic approach for PAD.