About event
Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder caused by dystrophin gene mutations. Skeletal muscle loss is followed by cardiac muscle deterioration and cardiomyopathy. Lack of effective treatment leads to only palliative care.
In addition to the widely accepted role of dystrophin in myocytes, DMD cells are affected from the pluripotent stem cell (PSC) state through differentiation toward cardiomyocytes. We have shown, that dystrophin-deficient PSCs present elevated DNA damage and mutagenesis, at least partially caused by deregulation of nitric oxide synthase (NOS) and subsequent production of reactive species. Further DMD cardiovascular progenitor (CP) populations show an altered transcriptional program with higher and earlier activation of CP markers with subsequent attenuation of their transcription and an earlier onset of transcription of genes associated with maturation coinciding with a decrease in proliferation in the organoid. DMD CPs also present higher levels of inflammation and DNA damage, thus recapitulating the phenotype of mdx mouse and human DMD hearts. These early deregulations are followed by impaired cardiac differentiation efficacy as illustrated by forming fewer spontaneously contracting organoids with a higher rate of cardiomyocyte (CM) death, increased content, and earlier collagen deposition. NOS inhibition attenuates DNA damage and improves beating organoid formation; however, it does not prevent CM death or significantly affect the transcription of cardiac development-related genes.
More information
This event is part of the Principal Investigator Seminar Series, the schedule of seminars can be found here.
