Abstract
BackgroundCongenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness. The two most prevalent forms of CMD, collagen VI-related myopathies (COL6RM) and laminin α2 deficient CMD type 1A (MDC1A), are both caused by deficiency or dysfunction of extracellular matrix proteins. Previously, we showed that an intramuscular transplantation of human adipose-derived stem cells (ADSC) into the muscle of the Col6a1−/− mice results in efficient stem cell engraftment, migration, long-term survival, and continuous production of the collagen VI protein, suggesting the feasibility of the systemic cellular therapy for COL6RM. In order for this therapeutic approach to work however, stem cells must be efficiently targeted to the entire body musculature. Thus, the main goal of this study is to test whether muscle homing of systemically transplanted ADSC can be enhanced by employing muscle-specific chemotactic signals originating from CMD-affected muscle tissue.MethodsProteomic screens of chemotactic molecules were conducted in the skeletal muscles of COL6RM- and MDC1A-affected patients and CMD mouse models to define the inflammatory and immune activities, thus, providing potential markers of disease activity or treatment effect. Also using a pre-clinical animal model, recapitulating mild Ullrich congenital muscular dystrophy (UCMD), the therapeutic relevance of identified chemotactic pathways was investigated in vivo, providing a basis for future clinical investigations.ResultsComprehensive proteomic screens evaluating relevant human and mouse skeletal muscle biopsies offered chemotactic axes to enhance directional migration of systemically transplanted cells into CMD-affected muscles, including CCL5-CCR1/3/5, CCL2-CCR2, CXCL1/2-CXCR1,2, and CXCL7-CXCR2. Also, the specific populations of ADSC selected with an affinity for the chemokines being released by damaged muscle showed efficient migration to injured site and presented their therapeutic effect.ConclusionsCollectively, identified molecules provided insight into the mechanisms governing directional migration and intramuscular trafficking of systemically infused stem cells, thus, permitting broad and effective application of the therapeutic adult stem cells for CMD treatment.
Highlights
Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness
Due to the distinct cellular origin of the proteins involved in the common CMD forms, even though a range of therapeutic approaches have been tested for traditional muscular dystrophies, there is a need to develop treatment strategies that target muscle extracellular matrix (ECM) alterations
Proteomic screens of chemokines in the skeletal muscles of CMD patients Proteome analysis consisted of skeletal muscle biopsies from patients with confirmed diagnosis of Bethlem Myopathy (BM, n = 5), Ulrich Congenital Muscular Dystrophy (UCMD, n = 8), and Merosin-deficient congenital muscular dystrophy type 1A (MDC1A, n = 5)
Summary
Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness. The two most prevalent forms of CMD, i.e., collagen VI (COL6)-related myopathies (COL6RM) and laminin α2 (LAMA2)-deficient CMD type 1A (MDC1A), share a similar underlying disease mechanism, consisting in the deficiency or dysfunction of extracellular matrix (ECM) proteins. Both disorders are unique among other hereditary myopathies and considered hybrid disorders with clinical features attributed to both muscle and connective tissue and oftencalled disorders of myomatrix. Due to the distinct cellular origin of the proteins involved in the common CMD forms, even though a range of therapeutic approaches have been tested for traditional muscular dystrophies, there is a need to develop treatment strategies that target muscle ECM alterations
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