cfaed Seminar Series

Muscle regeneration is governed by a complex crosstalk among dozen and more cell
types. Fibro-adipogenic precursors (FAPS) play an important role in this process by
positively regulating the activation and maturation of satellite cells, the muscle progenitor
cells. FAPs, however, when cultured i/n vitro/, show a remarkable capacity to differentiate
into adipocytes and fibroblasts. FAPs, indeed, are held responsible for the deposition of fat
and fibrotic infiltrates in the degenerating muscles of dystrophic or old individuals. Fat
depositions, however, are not observed in the interstitial regions between the fibers of
healthy muscles of young individuals.
We have modeled by a system of differential equation the process of muscle regeneration.
The model takes into account the complex network of interactions between the different
mononuclear cells that are resident in the muscle or are attracted to the muscle following
damage or chronic strain. This model faithfully represents the activation kinetic of the
different muscle cell types but predicts the accumulation of adipocytes, which is not
observed in physiological conditions. By purifying the different muscle cell types and by
testing them in pairwise combinations we have shown that myotubes negatively control
FAP differentiation by activating the NOTCH pathway. Remarkably adipogenesis of FAPs
from a murine dystrophy model cannot be controlled by the NOTCH ligand, providing a
rational basis for the observation that dystrophic patients, with age, accumulate fat and
scars in the muscle tissue. I will provide evidence of the molecular basis in this defect in
differentiation control.