HEREGULIN-INDUCED UTROPHIN UPREGULATION PROMOTES RECOVERY OF MUSCLE HOMEOSTASIS IN MDX MICE TRANSPLANTED WITH MICROENAPSULATED SERTOLI CELLS

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease characterized by progressive muscle degeneration ultimately leading to impaired locomotion and premature death. Due to the associated chronic inflammation DMD patients are treated with antiinflammatory steroids, albeit with limited efficacy and undesired side effects. We found that a single intraperitoneal (i.p.) transplantation of microencapsulated porcine Sertoli cells (SCs) [1] in mdx mice, an animal model of DMD, rescues muscle morphology and performance in the absence of pharmacological immunosuppression. Compared with muscles of mock-treated mice, muscles of SC-treated mice show a dramatic reduction of infiltrated inflammatory cells and fibrosis. While modulating the inflammatory response, SCs induce upregulation of the dystrophin paralogue, utrophin in muscle tissue thus promoting sarcolemma stability. We found that heregulin 1, a neuregulin-1 polypeptide capable of transactivating utrophin promoter and to ameliorate the dystrophic phenotype when i.p. injected in mdx mice [2], is expressed and secreted by porcine SCs. SC-treated mdx mice injected with a heregulin 1 blocking antibody fail to recover muscle morphology but show a marked reduction of infiltrated (MAC3+) macrophages as in the absence of antibody treatment, suggesting that the reduction of inflammation is a SC-mediated effect independent of heregulin 1-induced recovery of muscle morphology. Thus, i.p. transplantation of SCs in dystrophic mice restores muscle homeostasis due to combinatorial effects. Our results open new perspectives in the treatment of patients affected by DMD or related diseases. [1] Luca et al. Tissue Eng 13(2007):641-8; [2] Krag et al. Proc Natl Acad Sci USA 101(2004):13856-60.