Sertoli cells have promyogenic and antifibrotic effects, and induce utrophin expression in human DMD myotubes with different mutations in a heregulin β1/ErbB2/ERK1/2-dependent manner

Sertoli cells (SeC) are the major component of the seminiferous tubules, where they secrete a plethora of trophic and immunomodulatory factors necessary to development of germ cells [1]. For these characteristics, SeC have been widely used as a therapeutic approach in many pre-clinical studies, including Duchenne muscular dystrophy (DMD) [2,3]. DMD is a lethal, rare X-linked disease caused by mutation in the dystrophin gene (DMD). The absence of dystrophin compromises the integrity of the dystrophin glycoprotein complex (DGC) increasing susceptibility of sarcolemma to rupture during contraction, with consequent necrosis of myofibers and muscle chronic inflammation. In DMD patients, the contractile component of skeletal muscles is progressively replaced by adipose and fibrous tissues, compromising muscle functionality and leading to premature death [4]. Despite huge effort to find a cure, glucocorticoids remain the standard therapy for DMD patients, despite their limited efficacy and undesired side effects. We reported that a single intraperitoneal injection of microencapsulated porcine SeC translates into recovery of muscle morphology and performance in dystrophic mice. This was linked to the ability of SeC to restrain inflammation and upregulate the dystrophin paralogue, utrophin at the sarcolemma through the release of heregulin β1 [5,6]. Here, we report the direct effect of SeC on myoblasts/myotubes of murine origin or derived from healthy subjects and DMD patients with different mutations. We observed that SeC-secreted factors i) stimulate cell proliferation in the early phase of differentiation in C2C12, and human healthy and DMD myoblasts; ii) delay the expression of differentiation markers in the early phase, nevertheless stimulating terminal differentiation in DMD myoblasts; iii) restrain the fibrogenic phenotype in human fibroblasts, and inhibit myoblast-myofibroblast transdifferentiation in C2C12 cells treated with TGF-β, and in DMD myoblasts; iv) induce the upregulation of utrophin at the sarcolemma in DMD myotubes regardless of the mutation in a heregulin β1/ErbB2/ERK1/2-dependent manner, recruiting components of the DGC thus providing functional replacement of dystrophin. Altogether, these results further support the use of SeC as a potential treatment of DMD patients, and suggest that SeC might improve muscle regeneration, especially in the early phase when myoblasts have to proliferate to efficiently replace damaged myofibers.