Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration associated with chronic inflammation. Activation of inflammation-dependent pathways causes muscle necrosis and fibrosis, which represent the most deleterious outcome of DMD. Indeed, DMD patients are currently treated with antiinflammatory steroids, despite their limited efficacy and undesired side effects. Sertoli cells (SCs) are normally found in the testes where they couple trophic effects with prevention of immune damage to developing germ cells. Based on their ability to produce several immunomodulatory and trophic factors SCs have been successfully implanted to create an ectopic immune-privileged environment that prolongs survival of co-transplanted cells or restores systemic immune tolerance in autoimmune diseases (1). We transplanted SCs encapsulated in highly biocompatible microcapsules (2) in the peritoneal cavity of dystrophic, 4-week-old mdx mice. After 3 weeks, diaphragm, tibialis anterior and gastrocnemius muscles from SC- and mocktreated mice were examined. Compared to muscles from mock-treated mice, muscles from SCtreated mice showed: i) a dramatic reduction in necrotic areas and fibrous/adipose tissue infiltration; ii) reduced number of regenerating myofibers and increased number of regenerated and normal myofibers; iii) a marked reduction of infiltrated macrophages, activated (MyoD+) satellite cells and differentiating (myogenin+) myoblasts; iv) reduced expression of RAGE, a receptor that transduces inflammatory stimuli in immune cells and becomes re-expressed in muscle precursor cells and regenerating myofibers during early phases of muscle regeneration (3). Our data suggest that transplantation of microencapsulated SCs in dystrophic patients might be a useful therapeutic approach to counteract inflammation, thus creating a more suitable microenvironment for muscle regeneration. 1) Mital P. et al. 2010. Reproduction 139:495-504; 2) Luca G. et al. 2007. Tissue Eng 13:641-8; 3) Riuzzi F. et al. 2011. J Cell Sci, in revision.

Transplantation of microencapsulated Sertoli cells in mdx mice reduces muscle inflammation and promotes muscle regeneration

CHIAPPALUPI, SARA;SORCI, Guglielmo;LUCA, Giovanni;MANCUSO, FRANCESCA;CALVITTI, Mario;CALAFIORE, Riccardo;DONATO, Rosario Francesco
2011

Abstract

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration associated with chronic inflammation. Activation of inflammation-dependent pathways causes muscle necrosis and fibrosis, which represent the most deleterious outcome of DMD. Indeed, DMD patients are currently treated with antiinflammatory steroids, despite their limited efficacy and undesired side effects. Sertoli cells (SCs) are normally found in the testes where they couple trophic effects with prevention of immune damage to developing germ cells. Based on their ability to produce several immunomodulatory and trophic factors SCs have been successfully implanted to create an ectopic immune-privileged environment that prolongs survival of co-transplanted cells or restores systemic immune tolerance in autoimmune diseases (1). We transplanted SCs encapsulated in highly biocompatible microcapsules (2) in the peritoneal cavity of dystrophic, 4-week-old mdx mice. After 3 weeks, diaphragm, tibialis anterior and gastrocnemius muscles from SC- and mocktreated mice were examined. Compared to muscles from mock-treated mice, muscles from SCtreated mice showed: i) a dramatic reduction in necrotic areas and fibrous/adipose tissue infiltration; ii) reduced number of regenerating myofibers and increased number of regenerated and normal myofibers; iii) a marked reduction of infiltrated macrophages, activated (MyoD+) satellite cells and differentiating (myogenin+) myoblasts; iv) reduced expression of RAGE, a receptor that transduces inflammatory stimuli in immune cells and becomes re-expressed in muscle precursor cells and regenerating myofibers during early phases of muscle regeneration (3). Our data suggest that transplantation of microencapsulated SCs in dystrophic patients might be a useful therapeutic approach to counteract inflammation, thus creating a more suitable microenvironment for muscle regeneration. 1) Mital P. et al. 2010. Reproduction 139:495-504; 2) Luca G. et al. 2007. Tissue Eng 13:641-8; 3) Riuzzi F. et al. 2011. J Cell Sci, in revision.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11391/415495
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