Modulation of Stem Cell Differentiation and Myostatin as an Approach to Counteract Fibrosis in Muscle Dystrophy and Regeneration After Injury. Addendum
Abstract
We have investigated in the notexin-injured skeletal muscle of the aged mdx mouse a novel therapeutic approach for Duchenne s muscular dystrophy (DMD) based on the implantation of muscle-derived stem cells (MDSC), and the putative stimulation of their repair capacity by inhibition of myostatin (Mst) expression and/or activity, for the alleviation of fibrotic and fatty degeneration of the note xininjured dystrophic muscle. MDSC from the wild type mouse (WT MDSC), the myostatin knock-out mouse (Mst KO MDSC), and the mdx mouse (mdx MDSC) were compared. Concurrent pharmacological interventions were also tested with WT MDSC on skeletal muscle, and other tissues. We showed the repair capacity of MDSC to counteract fibrosis and the resulting dysfunction in several non-skeletal muscle tissues in other rat and mouse models, the pro-fibrotic effects of myostatin, and the antifibrotic effects of nitric oxide donors (molsidomine), PDE 5 inhibitors (sildenafil), and antioxidants (allopurinol), alone or in combination with WT MDSC. We found that WT MDSC are considerably myogenic in cell culture and stimulate muscle repair after injury in the aged mdx mouse, but that Mst KO MDSC are unable to form myotubes in vitro. However, their myogenic capacity is recovered in vivo under the influence of the myostatin+ host tissue environment, presumably by reactivation of key genes originally silenced in these cells. Our ongoing studies suggest that although myofibroblast generation may impair muscle tissue repair by WT MDSC, this may be counteracted with molsidomine, but not by antioxidants, and that the MDSC/molsidomine combination stimulates angiogenesis in the severely necrotic muscle of mice with limb ischemia.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2012
- Accession Number
- ADA586854
Entities
People
- Nestor F. Gonzalez-cadavid
Organizations
- Charles R. Drew University of Medicine and Science