Muscular Dystrophy Therapy by Nonautologous Mesenchymal Stem Cells: Muscle Regeneration Without Immunosuppression and Inflammation

Abstract

Background The use of non-autologous stem cells isolated from healthy donors for stem cell therapy is an attractive approach since the stem cells can be culture expanded in advance, thoroughly tested, and formulated into off-the-shelf medicine. However, HLA compatibility and related immunosuppressive protocols can compromise therapeutic efficacy and cause unwanted side effects. Methods Mesenchymal stem cells (MSCs) have been postulated to possess unique immune regulatory function. We explored the immunomodulatory property of human and porcine MSCs for the treatment of δ-sarcoglycan-deficient dystrophic hamster muscle without immunosuppression. Circulating as well as tissue markers of inflammation were analyzed. Muscle regeneration and stem cell fate were characterized. Results Total white blood cell counts and leukocyte distribution profiles were similar among the saline- and MSC-injected dystrophic hamsters one month post treatment. Circulating levels of immunoglobulin A, vascular cell adhesion molecule-1, myeloperoxidase, and major cytokines involved in inflammatory response were not elevated by MSCs, nor were expression of the leukocyte common antigen CD45 and the cytokine transcriptional activator NF-κB in the injected muscle. Treated muscles exhibited increased cell cycle activity and attenuated oxidative stress. Injected MSCs were found to be trapped in the musculature, and contribute to both preexisting and new muscle fibers, and mediates capillary formation. Conclusions Intramuscular injection of non-autologous MSCs can be safely used for the treatment of dystrophic muscle in immunocompetent hosts without inflaming the host immune system.

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

“…Instead, it is believed that MSCs exert their therapeutic effects through secreted paracrine or trophic factors [15][16][17]. Experiments utilizing MSC-conditioned media have demonstrated the importance of the paracrine mechanism of BM-MSC-induced wound healing [49][50][51][52].…”

“…Instead it is believed that MSCs exert their therapeutic effects by secreting soluble or ''paracrine'' factors that augment endogenous repair and regenerative mechanisms [15][16][17][18]. Also, work in our laboratory has found that MSCs can enhance fibroblast migration, an integral component of the wound healing process, without direct contact, suggesting the importance of paracrine signaling between these cells [19].…”

Fetal Liver-Derived Mesenchymal Stem Cell Engraftment After Allogeneic In Utero Transplantation into Rabbits

“…For example, prenatal tolerance induction has been a main goal of in utero hematopoietic stem cell transplantation, to facilitate postnatal cellular transplantation [2,3]. Due to their recently described multilineage differentiation, and regenerative and immunomodulatory capabilities, mesenchymal stem cells (MSCs) are also being actively explored for the treatment of established nonhematopoietic diseases, including musculoskeletal defects [4][5][6][7], and to improve hematopoietic stem cell engraftment [8].…”

Enhancing the efficacy of mesenchymal stem cell therapy

“…Thus, intracoronary infusion of MSCs for heart therapy, which retained only 1%-2% of the infused cells in the porcine myocardium, was found to result in significant functional improvement in the hibernating myocardium [112,113] . The recognition that IL-6 and IL-6-type cytokines are abundantly produced by MSCs [6,55] and that skeletal muscle actively induces IL-6 during exercise [56,114] prompted us to pioneer an intramuscular (im) MSC delivery route for cardiac repair [6,30,115] . This im MSC therapeutic strategy is coupled to the inherent ability of skeletal muscle to produce beneficial trophic factors in response to exercise and injury [116][117][118] , and therefore represents an integrative physiological approach.…”