MyoD Expression Restores Defective Myogenic Differentiation of Human Mesoangioblasts from Inclusion-Body Myositis Muscle

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-11, Vol.103 (45), p.16995-17000
• Main Authors: Morosetti, Roberta, Mirabella, Massimiliano, Gliubizzi, Carla, Broccolini, Aldobrando, De Angelism, Luciana, Tagliafico, Enrico, Sampaolesi, Maurilio, Gidaro, Teresa, Papacci, Manuela, Roncaglia, Enrica, Rutella, Sergio, Ferrari, Stefano, Tonali, Pietro Attilio, Ricci, Enzo, Cossu, Giulio
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase - metabolism; Basic Helix-Loop-Helix Transcription Factors - antagonists & inhibitors; Basic Helix-Loop-Helix Transcription Factors - genetics; Biological Sciences; Biopsies; Cell Differentiation; Cells, Cultured; Cellular differentiation; Connective tissues; Gene Expression; Gene Silencing; Humans; Inflammatory diseases; Medical treatment; Muscle Development; Muscle fibers; Muscle, Skeletal - blood supply; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Muscular system; Myoblasts, Skeletal - metabolism; Myoblasts, Skeletal - pathology; MyoD Protein - genetics; MyoD Protein - metabolism; Myositis; Myositis, Inclusion Body - metabolism; Myositis, Inclusion Body - pathology; Myositis, Inclusion Body - therapy; Neurosciences; RNA, Small Interfering - genetics; Skeletal muscle; Skeletal muscle satellite cells; Small interfering RNA
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0603386103

Inflammatory myopathies (IM) are acquired diseases of skeletal muscle comprising dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). Immunosuppressive therapies, usually beneficial for DM and PM, are poorly effective in IBM. We report the isolation and characterization of mesoangioblasts, vessel-associated stem cells, from diagnostic muscle biopsies of IM. The number of cells isolated, proliferation rate and lifespan, markers expression, and ability to differentiate into smooth muscle do not differ among normal and IM mesoangioblasts. At variance with normal, DM and PM mesoangioblasts, cells isolated from IBM, fail to differentiate into skeletal myotubes. These data correlate with lack in connective tissue of IBM muscle of alkaline phosphatase (ALP)-positive cells, conversely dramatically increased in PM and DM. A myogenic inhibitory basic helix-loop-helix factor B3 is highly expressed in IBM mesoangioblasts. Indeed, silencing this gene or overexpressing MyoD rescues the myogenic defect of IBM mesoangioblasts, opening novel cell-based therapeutic strategies for this crippling disorder.