title: Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice.
abstract: Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive muscle degeneration leading to impaired locomotion, respiratory failure and premature death. In DMD patients, inflammatory events secondary to dystrophin mutation play a major role in the progression of the pathology. Sertoli cells (SeC) have been largely used to protect xenogeneic engraftments or induce trophic effects thanks to their ability to secrete trophic, antiinflammatory, and immunomodulatory factors. Here we have purified SeC from specific pathogen-free (SPF)-certified neonatal pigs, and embedded them into clinical grade alginate microcapsules. We show that a single intraperitoneal injection of microencapsulated SPF SeC (SeC-MC) in an experimental model of DMD can rescue muscle morphology and performance in the absence of pharmacologic immunosuppressive treatments. Once i.p. injected, SeC-MC act as a drug delivery system that modulates the inflammatory response in muscle tissue, and upregulates the expression of the dystrophin paralogue, utrophin in muscles through systemic release of heregulin-β1, thus promoting sarcolemma stability. Analyses performed five months after single injection show high biocompatibility and long-term efficacy of SeC-MC. Our results might open new avenues for the treatment of patients with DMD and related diseases.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy; Interuniversity Institute of Myology (IIM), Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Chiappalupi
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Luca
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancuso
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome 00143, Italy; National Research Council, Institute of Cell Biology and Neurobiology, Fondazione Santa Lucia, Rome 00143, Italy; Interuniversity Institute of Myology (IIM), Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Madaro
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Unit of Histology, DAHFMO, La Sapienza University, Rome 00161, Italy; Interuniversity Institute of Myology (IIM), Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Nicoletti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Calvitti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.
authors.forename: Iva
authors.initials: I
authors.lastname: Arato
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Falabella
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Salvadori
authors.affiliation: Department of Veterinary Medicine, University of Perugia, Perugia 06126, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Meo
authors.affiliation: Department of Veterinary Medicine, University of Perugia, Perugia 06126, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Bufalari
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Perugia 06123, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Giovagnoli
authors.affiliation: Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Calafiore
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy; Interuniversity Institute of Myology (IIM), Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Donato
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy; Interuniversity Institute of Myology (IIM), Italy. Electronic address: guglielmo.sorci@unipg.it.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Sorci
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002908:Chronic Disease; D004339:Drug Compounding; D006706:Homeostasis / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D018101:Mice, Inbred mdx; D009132:Muscles / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000473:pathology* / Q000503:physiopathology; D020890:Neuregulin-1 / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects; D012708:Sertoli Cells / Q000166:cytology / Q000637:transplantation*; D034421:Sus scrofa; D015854:Up-Regulation / Q000187:drug effects; D049411:Utrophin / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D020890:Neuregulin-1; D049411:Utrophin; C087230:heregulin beta1
keywords: Duchenne muscular dystrophy; Engraftment; Heregulin; Microencapsulation; SPF; Sertoli cells