Congenital Muscular Dystrophy-Associated Inflammatory Chemokines Provide Axes for Effective Recruitment of Therapeutic Adult Stem Cell into Muscles

Abstract

Background: 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, collagen VI-related myopathies (COL6RM) and laminin a2 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. Methods: Proteomic 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. Results: Comprehensive 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.Conclusions: Collectively, identified molecules provided insight into the mechanisms governing directional migration and intra-muscular trafficking of systemically infused stem cells, thus, permitting broad and effective application of the therapeutic adult stem cells for CMD treatment.

Collagen VI as a driver and disease biomarker in human fibrosis

“…[109] Increased lung tissue elasticity, altered airway morphology; larger but fewer alveoli and increased epithelium thickening [48][49][50] Decreased intracranial melanoma progression, basal laminin deposition and pericyte maturation and vascular defects [200] Col1a1 collagen VI-related myopathies (CMD) and Col6a1 À/À mice to identify chemokines/chemokine receptors which could be specifically activated to promote disease-specific homing of the circulating ADSC to skeletal muscle [61]. CCR2 and CXCR2 emerged as putative targets, as they provided directional migration of the ADSC into injured muscle in CDM murine models.…”

“…However, an effective therapy would require transplantation of ADSC to the entire musculature. The team recently performed a proteomic screen using muscle biopsies from patients with collagen VI‐related myopathies (CMD) and Col6a1 −/− mice to identify chemokines/chemokine receptors which could be specifically activated to promote disease‐specific homing of the circulating ADSC to skeletal muscle [61]. CCR2 and CXCR2 emerged as putative targets, as they provided directional migration of the ADSC into injured muscle in CDM murine models.…”