Human adipose-derived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy

Abstract

IntroductionCongenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness within the first two years of life. Collagen VI-related muscle disorders have recently emerged as one of the most common types of CMD. COL6 CMD is caused by deficiency and/or dysfunction of extracellular matrix (ECM) protein collagen VI. Currently, there is no specific treatment for this disabling and life-threatening disease. The primary cellular targets for collagen VI CMD therapy are fibroblasts in muscle, tendon and skin, as opposed to muscle cells for other types of muscular dystrophies. However, recent advances in stem cell research have raised the possibility that use of adult stem cells may provide dramatic new therapies for treatment of COL6 CMD.MethodsHere, we developed a procedure for isolation of human stem cells from the adipose layer of neonatal skin. The adipose-derived stem cells (ADSC) were examined for expression of ECM and related genes using gene expression array analysis. The therapeutic potential of ADSC was assessed after a single intramuscular transplantation in collagen VI-deficient mice.ResultsAnalysis of primary cultures confirmed that established ADSC represent a morphologically homogenous population with phenotypic and functional features of adult mesenchymal stem cells. A comprehensive gene expression analysis showed that ADSC express a vast array of ECM genes. Importantly, it was observed that ADSC synthesize and secrete all three collagen VI chains, suggesting suitability of ADSC for COL6 CMD treatment. Furthermore, we have found that a single intramuscular transplantation of ADSC into Col6a1−/−Rag1−/− mice under physiological and cardiotoxin-induced injury/regeneration conditions results in efficient engraftment and migration of stem cells within the skeletal muscle. Importantly, we showed that ADSC can survive long-term and continuously secrete the therapeutic collagen VI protein missing in the mutant mice.ConclusionsOverall, our findings suggest that stem cell therapy can potentially provide a new avenue for the treatment of COL6 CMD and other muscular disorders and injuries.

Adipose-Derived Stromal Cells from Lipomas: Isolation, Characterisation and Review of the Literature

“…The presence of ADSCs in lipomas with a differentiation potential similar to that of regular ADSCs has been shown in previous studies [11,12,16,17]. Potentially, ADSCs from useless tissue may be an attractive cell source for the application of regenerative medicine [18]. The cells residing in fat stroma revealed a wide range of functional properties in vivo as well as differentiation potential in vitro.…”

“…Thus, stem cell-based therapy hold promise for treating acquired and genetic diseases and has been utilized in animal models and human clinical trials, such as wound healing, tissue repair, cardiovascular disorders [19], congenital muscular dystrophy [18] or lower genito-urinary dysfunction [20]. …”

Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)

“…Furthermore, multipotent mesenchymal stem cell (MSC) is the most common type of adult stem cells and is isolated from several sources such as bone marrow and adipose tissue. Another report has recently shown that transplanted human adipose-derived stem cells, with phenotypic and functional features of mesenchymal progenitors, secrete collagen VI protein in Col6a1 −/− mice 59. Thus, MSC-based therapy can be an attractive option as transplanted cells are able to self-renew and to differentiate into collagen VI-producing cells in skeletal muscle 41 42…”

148 Therapeutic Effects of Adipose-Derived Stem Cells-Based Micro-Tissues on Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats

“…22 Moreover, they have been applied to repair muscle tissues and restore tissue vascularization. 25 As for ED therapy, independent groups have investigated the feasibilities and advantages of ADSCs in rat models of DMED, cavernous nerve injury, and Peyronie's disease. 16,26,27 These results were encouraging but the traditional single-cell-based injection was relative preliminary, and the therapeutic potential was hampered by poor retention rate due to the blood flow.…”