Duchenne muscular dystrophy (DMD) is too often considered as an affection of male children. Symptoms appear in early childhood, with a diagnosis made around 4, a time where the amount of muscle damage is already significant, preventing early therapeutic interventions that could be more efficient at halting disease progression. Thus, there is a critical need to better define DMD onset as well as its first manifestations, which could help identify early disease biomarkers and novel therapeutic targets.
We have used human induced pluripotent stem cells (hiPSCs) from DMD patients to model embryonic/foetal skeletal myogenesis, and compared their differentiation dynamics to healthy control cells by a comprehensive multi-omics analysis.

Transcriptome and miRnome comparisons combined with protein analyses demonstrate that hiPSC skeletal muscle differentiation 1) mimics known DMD phenotypes at the differentiation endpoint; 2) homogeneously and robustly recapitulates key developmental steps – mesoderm, somite, skeletal muscle – which offers the possibility to explore dystrophin functions and find earlier disease biomarkers; and 3) that the skeletal muscle precursors cells obtained with, are compatible with high-throughput experiments, thus increasing the capability of drug screening.

Moreover, our data strongly argue for an early developmental manifestation of DMD whose onset is triggered at the somite stage before the entry into the skeletal muscle compartment. And we describe fibrosis as an intrinsic feature of skeletal muscle cells that also starts early during myogenesis. Dystrophin functions during development need to be reconsidered.

For more information on this talk or iStem’s visit to Oxford, please visit: www.onmc.ox.ac.uk/events/seminar-human-ipscs-dmd-onset-mechanisms-therapies-development