Sertoli cells (SeC) are the major component of the seminiferous tubules, where they secrete trophic and immunomodulatory factors necessary to protect developing germ cells.1 Based on their peculiar properties, many preclinical studies have reported the successful employment of SeC in different pathologies, including Duchenne muscular dystrophy (DMD).1-3 We demonstrated that a single i.p. injection of microencapsulated porcine SeC, in the absence of pharmacological immunosuppression, induces the recovery of muscle morphology and performance in dystrophic mice, thanks to two independent effects: the release of antiinflammatory/trophic factors, and the release of heregulin β1 that upregulates the dystrophin paralogue, utrophin at the sarcolemma.3,4 The direct effects of SeC on myoblasts/myotubes have not been investigated so far. We found that SeC-derived factors i) stimulate cell proliferation in the early phase of the differentiation process in C2C12 and human healthy and DMD myoblasts; ii) delay the expression of differentiation markers in the early phase, and stimulate terminal differentiation in DMD myoblasts; iii) restrain the fibrogenic phenotype in human fibroblasts, and inhibit myofibroblast transdifferentiation in C2C12 and healthy and 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. Altogether, our results suggest that the SeC-based treatment is equivalent to a combinatorial approach with beneficial effects on the myoblast and fibroblast components of dystrophic muscles, and represents a universal (i.e., mutation-independent) approach to DMD. Moreover, SeC might be beneficial during the early phase of muscle regeneration when myoblasts have to proliferate to efficiently replace damaged myofibers. 1. Luca G, Arato I, Sorci G, Cameron DF, Hansen BC, Baroni T, Donato R, White DGJ, Calafiore R. Sertoli cells for cell transplantation: pre-clinical studies and future perspectives. Andrology. 2018 May;6(3):385-395. 2. Washburn RL, Hibler T, Thompson LA, Kaur G, Dufour JM. Therapeutic application of Sertoli cells for treatment of various diseases. Semin Cell Dev Biol. 2021 Apr 25:S1084-9521(21)00080-X. 3. Chiappalupi S, Salvadori L, Luca G, Riuzzi F, Calafiore R, Donato R, Sorci G. Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy. J Funct Morphol Kinesiol. 2017;2(4):47. 4. Chiappalupi S, Luca G, Mancuso F, Madaro L, Fallarino F, Nicoletti C, Calvitti M, Arato I, Falabella G, Salvadori L, Di Meo A, Bufalari A, Giovagnoli S, Calafiore R, Donato R, Sorci G. Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice. Biomaterials. 2016 Jan;75:313-326.
Sertoli cells induce utrophin expression in human DMD myotubes with different mutations and exert promyogenic and antifibrotic effects
Chiappalupi S.
;Salvadori L.;Arato I.;Mancuso F.;Calvitti M.;Marchetti C.;Riuzzi F.;Calafiore R.;Luca G.;Sorci G
2021
Abstract
Sertoli cells (SeC) are the major component of the seminiferous tubules, where they secrete trophic and immunomodulatory factors necessary to protect developing germ cells.1 Based on their peculiar properties, many preclinical studies have reported the successful employment of SeC in different pathologies, including Duchenne muscular dystrophy (DMD).1-3 We demonstrated that a single i.p. injection of microencapsulated porcine SeC, in the absence of pharmacological immunosuppression, induces the recovery of muscle morphology and performance in dystrophic mice, thanks to two independent effects: the release of antiinflammatory/trophic factors, and the release of heregulin β1 that upregulates the dystrophin paralogue, utrophin at the sarcolemma.3,4 The direct effects of SeC on myoblasts/myotubes have not been investigated so far. We found that SeC-derived factors i) stimulate cell proliferation in the early phase of the differentiation process in C2C12 and human healthy and DMD myoblasts; ii) delay the expression of differentiation markers in the early phase, and stimulate terminal differentiation in DMD myoblasts; iii) restrain the fibrogenic phenotype in human fibroblasts, and inhibit myofibroblast transdifferentiation in C2C12 and healthy and 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. Altogether, our results suggest that the SeC-based treatment is equivalent to a combinatorial approach with beneficial effects on the myoblast and fibroblast components of dystrophic muscles, and represents a universal (i.e., mutation-independent) approach to DMD. Moreover, SeC might be beneficial during the early phase of muscle regeneration when myoblasts have to proliferate to efficiently replace damaged myofibers. 1. Luca G, Arato I, Sorci G, Cameron DF, Hansen BC, Baroni T, Donato R, White DGJ, Calafiore R. Sertoli cells for cell transplantation: pre-clinical studies and future perspectives. Andrology. 2018 May;6(3):385-395. 2. Washburn RL, Hibler T, Thompson LA, Kaur G, Dufour JM. Therapeutic application of Sertoli cells for treatment of various diseases. Semin Cell Dev Biol. 2021 Apr 25:S1084-9521(21)00080-X. 3. Chiappalupi S, Salvadori L, Luca G, Riuzzi F, Calafiore R, Donato R, Sorci G. Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy. J Funct Morphol Kinesiol. 2017;2(4):47. 4. Chiappalupi S, Luca G, Mancuso F, Madaro L, Fallarino F, Nicoletti C, Calvitti M, Arato I, Falabella G, Salvadori L, Di Meo A, Bufalari A, Giovagnoli S, Calafiore R, Donato R, Sorci G. Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice. Biomaterials. 2016 Jan;75:313-326.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
