Systemic Delivery of Human Mesenchymal Stromal Cells Combined with IGF-1 Enhances Muscle Functional Recovery in LAMA2 dy/2j Dystrophic Mice
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The combination of cell therapy with growth factors could be a useful approach to treat progressive muscular dystrophies. Here, we demonstrate, for the first time, that IGF-1 considerably enhances the myogenesis of human umbilical cord (UC) mesenchymal stromal cells (MSCs) in vitro and that IGF-1 enhances interaction and restoration of dystrophin expression in co-cultures of MSCs and muscle cells from Duchenne patients. In vivo studies showed that human MSCs were able to reach the skeletal muscle of LAMA2 dy/2j dystrophic mice, through systemic delivery, without immunosuppression. Moreover, we showed, for the first time, that IGF-1 injected systemically together with MSCs markedly reduced muscle inflammation and fibrosis, and significantly improved muscle strength in dystrophic mice. Our results suggest that a combined treatment with IGF-1 and MSCs enhances efficiency of muscle repair and, therefore, should be further considered as a potential therapeutic approach in muscular dystrophies.
KeywordsMuscular dystrophies IGF-1 Mesenchymal stromal cells
Members from University Hospital, Constancia Urbani, Marcos Valadares, Tatiana Jazedje, Estela Cruvinel, Carla Freitas, Juliana Gomes, Amanda Assoni, Gabriela Polster, Heloisa Caetano, Tabata Leal, Maria Neide Mascarenhas, Miriam Suzuki, Paula Onofre, Marta Canovas, Fernando Luis Molina and Maria Rita Passos-Bueno are gratefully acknowledged for support and for helpful suggestions. We would like to thank Dr. Glenn Morris from the Center for Inherited Neuromuscular Disease (CIND) - UK for providing anti-human dystrophin antibody. This work was supported with grants of CEPID-FAPESP (Centro de Pesquisa, Inovação e Difusão-Fundação de Amparo a Pesquisa do Estado de São Paulo), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), INCT (Instituto Nacional de Ciência e Tecnologia). The authors indicate no potential conflicts of interest.
The authors indicate no potential conflicts of interest.
- 11.Vieira, N. M., Valadares, M., Zucconi, E., et al. (2011). Human adipose-derived mesenchymal stromal cells injected systemically into GRMD dogs without immunosupression are able to reach the host muscle and express human dystrophin. Cell Transplantation. doi: 10.3727/096368911X603648.
- 13.da Justa Pinheiro, C. H., de Queiroz, J. C., Guimarães-Ferreira, L., et al. (2011). Local injections of adipose-derived mesenchymal stem cells modulate inflammation and increase angiogenesis ameliorating the dystrophic phenotype in dystrophin-deficient skeletal muscle. Stem Cell Reviews and Reports. doi: 10.1007/s12015-011-9304-0.
- 14.Zucconi, E., Vieira, N. M., Bueno, C. R., et al. (2011). Preclinical studies with umbilical cord mesenchymal stromal cells in different animal models for muscular dystrophy. Journal of Biomedicine and Biotechnology. doi: 10.1155/2011/715251.
- 38.Lee, M. J., Jung, J., Na, K. H., et al. (2010). Anti-fibrotic effect of chorionic plate-derived mesenchymal stem cells isolated from human placenta in a rat model of CCl(4)-injured liver: potential application to the treatment of hepatic diseases. Journal of Cellular Biochemistry, 111, 1453–1463.PubMedCrossRefGoogle Scholar
- 39.Scicchitano, B. M., Rizzuto, E., & Musarò, A. (2009). Counteracting muscle wasting in aging and neuromuscular diseases: the critical role of IGF-1. Aging (Albany NY), 1, 451–457.Google Scholar