Abstract
Muscle disease leads to significant mortality and morbidity worldwide, and few effective treatment options are available. Bone marrow-derived mesenchymal stem cells (MSCs) offer a highly attractive means of cell therapy, having multiple modes of action, accessible, at low risk of malignant transformation and amenable to autologous transplantation. Engraftment of transplanted MSCs into skeletal muscle has been demonstrated but spontaneous incorporation is low. The factors influencing MSC myogenicity are not fully defined, and if better understood could markedly improve therapeutic prospects. Here, we identified growth factors and culture conditions that showed significant promise in promoting myogenic differentiation of human MSCs. Culture on collagen; using skeletal muscle media (containing dexamethasone, insulin, EGF, bovine fetuin, bovine serum albumin and gentamicin); and exposure to a combination of IGF1, FGF2 and VEGF all selectively increased myogenic marker transcript expression by human MSCs. Initiating and sustaining myogenic differentiation of MSCs in vitro may be a critical step in harnessing these cells for therapy. We also showed that human MSCs aggregate with myoblasts in vitro and appear to form multi-nucleated structures expressing a range of skeletal muscle markers. Our observations provide further evidence that MSCs are a credible candidate for cellular therapy in patients with muscle disease.
Highlights
Primary muscle diseases include muscular dystrophies, inflammatory and metabolic myopathies, mitochondrial cytopathies, channelopathies and other inherited diseases
We showed that human mesenchymal stem cells (MSCs) aggregate with myoblasts in vitro and appear to form multi-nucleated structures expressing a range of skeletal muscle markers
We explored the influence on (i) morphology, (ii) antigen expression assessed by immunofluorescence, and (iii) transcript expression assessed by real time PCR of three sets of manipulations – growth in conventional MSC or ‘basal’ culture medium; the addition of specific growth factors alone or in combination, or of various types of conditioned medium; growth on a collagen substrate; and growth in co-culture conditions with various muscle-related cell types, as described below
Summary
Primary muscle diseases include muscular dystrophies, inflammatory and metabolic myopathies, mitochondrial cytopathies, channelopathies and other inherited diseases. There is increasing recognition that secondary muscle dysfunction – from aging, immobility, critical illness, trauma, denervation, cancer and other metabolic abnormalities – is a major cause of muscle-related morbidity. These muscle diseases cause major disability, often with few if any treatment options, and the prospect of stem cell therapies has generated much interest [1]. Bone marrow-derived mesenchymal stem cells (MSCs) are an attractive prospect, being multipotent, relatively accessible, of low malignancy potential, and open to autologous transplantation [2]. Spontaneous incorporation of these cells is low Enhancing their myogenic potential could markedly improve therapeutic prospects, but those factors regulating this differentiation remain incompletely understood
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