Long-term effectiveness of local BM-MSCs for skeletal muscle regeneration: a proof of concept obtained on a pig model of severe radiation burn

• Published in: Stem cell research & therapy Vol. 9; no. 1; pp. 299 - 14
• Main Authors: Linard, Christine, Brachet, Michel, L’homme, Bruno, Strup-Perrot, Carine, Busson, Elodie, Bonneau, Michel, Lataillade, Jean-Jacques, Bey, Eric, Benderitter, Marc
• Format: Journal Article
• Language: English
• Published: London BioMed Central 08.11.2018; BioMed Central Ltd; BMC
• Subjects: Angiogenesis; Animals; Antigens, CD34 - metabolism; Autografts; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; BM-MSC; Bone marrow; Bone Marrow Cells - cytology; Bone surgery; Burns - pathology; Burns - physiopathology; Burns - therapy; Calcium signalling; Capillaries; Care and treatment; Cell Biology; Cell cycle; Cell Differentiation - genetics; Collagen; Degeneration; Disease Models, Animal; Excision (Surgery); Extracellular Matrix - metabolism; Fibroblasts; Gangrene; Gene expression; Gene Expression Regulation; Growth factors; Health aspects; Inflammation; Injections; Irradiation; Life Sciences; Macrophages; Macrophages - metabolism; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - cytology; Mesenchyme; Muscle; Muscle Fibers, Skeletal - pathology; Muscle regeneration; Muscle, Skeletal - blood supply; Muscle, Skeletal - physiopathology; Muscular dystrophy; Musculoskeletal system; Oxidative stress; Phenotype; Pig; Plastic surgery; Radiation; Radiation Injuries - pathology; Radiation Injuries - physiopathology; Radiation Injuries - therapy; Regeneration; Regenerative Medicine/Tissue Engineering; Skeletal muscle; Skin; Stem Cells; Stromal cells; Swine; Time Factors; Trauma; Treatment Outcome; Vascular endothelial growth factor; Wound healing; Irradiation; Regeneration; BM-MSC; Muscle; Pig
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-018-1051-6

Background Medical management of the severe musculocutaneous radiation syndrome involves surgical intervention with debridement of necrotic tissue. Even when skin excision is replaced by specific plastic surgery, treatment of the muscle radiation injury nonetheless remains difficult, for it involves a massive muscle defect in an unpredictable environment, subject to inflammatory waves weeks to months after irradiation, which delay healing and predispose the patient to the development of fibrous scar tissue. In this study, we investigated the long-term effect of local injections of bone marrow-derived mesenchymal stromal cells (BM-MSCs), combined with plastic surgery, to treat muscle necrosis in a large animal model. Methods Three months after irradiation to the rump, minipigs were treated by excision of necrotic muscle tissue, vascularized flap surgery, and four injections with or without local autologous BM-MSCs, performed weekly. The quality of the muscle wound healing was examined 1 year post-surgery. Results The skeletal muscle surgery without MSC treatment led to permanent deposition of collagen 1 and 3, decreased myofiber diameter, failed muscle fiber regeneration, a reduced number of capillaries, and the accumulation of high calcium and fat. In animals treated by surgery and MSC injections, these indicators were substantially better and demonstrated established regeneration. MSC therapy acts at several levels by stimulating growth factors such as VEGF, which is involved in angiogenesis and satellite cell pool maintenance, and creating a macrophage M1/M2 balance. Conclusion Thus, cell therapy using BM-MSCs is an effective and safe way to improve recovery of irradiation-induced skeletal muscle damage without signs of long-term degeneration.