Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

Abstract

We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1].

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

“…The i.p. injection of MC-SeC had similar positive effects even on muscles of chronic (12 months of age) mdx mice, and resulted protective against muscle necrosis and inflammation in presymptomatic (two weeks of age) animals [122].…”

Sertoli Cells Improve Myogenic Differentiation, Reduce Fibrogenic Markers, and Induce Utrophin Expression in Human DMD Myoblasts

“…MC-SeC injected into the peritoneal cavity of dystrophic (mdx) mice proved to be beneficial in recovering muscle homeostasis thanks to the release of a cocktail of factors that counteract muscle inflammation and fibrosis, and the induction of the expression of the dystrophin paralogue, utrophin at the sarcolemma of myofibers [11,12]. However, data about the effects of SeC on satellite cells (i.e., the adult stem cells of skeletal muscle residing between the basal lamina and the plasmalemma [35]) and their progeny, the myoblasts, were not available.…”

“…We set up a therapeutic approach [11,12] based on the peculiar properties of Sertoli cells (SeC), a cell type of the seminiferous tubules of the testis in which they favor the maturation of developing germ cells and protect them against the host immune system [13]. Besides creating a physical barrier (the blood-testis barrier), SeC secrete a plethora of trophic and immunomodulatory factors that confer to these cells the ability to survive long time after engraftment, and protect allo-and xenogenic engraftments of tissues and organs [14][15][16].…”

“…Besides creating a physical barrier (the blood-testis barrier), SeC secrete a plethora of trophic and immunomodulatory factors that confer to these cells the ability to survive long time after engraftment, and protect allo-and xenogenic engraftments of tissues and organs [14][15][16]. SeC isolated from specific pathogens free (SPF) pre-pubertal pigs were encapsulated in highly biocompatible alginate-based microcapsules (MC-SeC) and injected into the peritoneal cavity of mdx mice, an experimental model of DMD, in the absence of pharmacological immunosuppression [11,12]. A single injection of MC-SeC resulted in amelioration of muscle morphology and performance as a consequence of the secretion by SeC, from the peritoneal cavity into the bloodstream, of anti-inflammatory factors and heregulin β1, an inducer of the dystrophin paralogue, utrophin.…”

“…A single injection of MC-SeC resulted in amelioration of muscle morphology and performance as a consequence of the secretion by SeC, from the peritoneal cavity into the bloodstream, of anti-inflammatory factors and heregulin β1, an inducer of the dystrophin paralogue, utrophin. Short-and longterm beneficial effects of MC-SeC treatment (i.e., reduction of inflammatory infiltrate, re-expression of utrophin at the sarcolemma, and reduced necrosis of myofibers) have been reported in several muscles, including the diaphragm, thus opening new perspectives in the treatment of DMD [11,12]. Here, we have investigated the effects of SeC on muscle precursor cells, with particular regards to human healthy and DMD myoblasts/myotubes as a necessary step in view of a potential application of SeC-based treatments to DMD.…”