Seminar Information

Speaker:

Diego Fraidenraich, PhD
Director of Stem Cell Research
New Jersey Medical School
UMDNJ

Title:

Correction of muscular dystrophy in mice by blastocyst injection of murine induced pluripotent stem cells

Abstract:

Duchenne muscular dystrophy (DMD) is an incurable neurodegenerative disease. We injected mouse WT induced pluripotent stem (iPS) cells into mdx and mdx:utrophin mutant blastocysts, which are predisposed to develop DMD. 20-40% of incorporation of iPS cells led to a significant amelioration of the disease at the morphological and functional levels.

In the mdx rescue, dystrophin is supplied to heart and muscle. This leads to a reassembly of the dystrophin-glycoprotein complex. Mdx mice are lean, but incorporation of iPS cells rescues the fat mass phenotype, even though the fat does not express dystrophin. In turn, the fat secretes Wnt and follistatin-like factors, which may impact on the hypertrophic state of the chimeric muscle.

In the mdx:utro double mutants, chimeric mice survive early demise, with concomitant gain in body weight. Dystrophin and utrophin are supplied to the heart and muscle (sarcolemma, neuromuscular junction and terminal axons). Morphological amelioration of the muscle phenotype is apparent, but mice still display kyphosis, suggesting that the skeleton and skeletal muscle require different thresholds of iPS cell incorporation to achieve corrections. The muscle of mdx:utro mice does not show regeneration activity and is smaller, but incorporation of iPS cells reactivate regeneration in fiber areas not containing iPS cell-derived dystrophin with concomitant gain in muscle mass. Fat also regains mass.

Thus, developmental injection of iPS cells ameliorates DMD in mice.