Role of mesenchymal fibro/adipogenic progenitors in homeostasis and disease: from signaling to fibrosis

Mesenchymal fibro/adipogenic progenitors (FAPs) are the cell source of myofibroblasts and adipocytes during muscular dystrophy (MD) and chronic muscle damage, but also important players for proper tissue regeneration. The best-known marker for FAPs is the receptor tyrosine kinase PDGFRα. TGF-β signaling pathway drives the fibrotic process inducing FAP proliferation and myofibroblast differentiation.

In the present Ph.D. thesis, we focused on the study of TGF-β signaling pathway and its role in FAP fate. On the other hand, canonical Wnt Tcf/Lef transcription factors are important players during development and controlling stem cell fate. The role of Tcf/Lef proteins in FAPs has not been studied yet. Recently, the canonical Wnt cascade emerged as a new system to study fibrosis. Whether TGF-β has an impact on Wnt signaling and/or may crosstalk through the regulation of Tcf/Lefs has not been explored yet.

The main findings of this Ph.D. Thesis are:
1. FAPs are present in skeletal muscle under normal conditions and are increased in several muscle models where fibrosis and TGF-β are a hallmark.
2. We suggest that the historically named muscle connective tissue fibroblast isolated via pre-plating correspond to a phenotypically and biochemically FAP-like population of adherent fibroblasts.
3. We described the role and/or cross-talk of TGF-β signaling in the regulation of PDGFR expression and signaling in mesenchymal progenitors.
4. TGF-β suppresses the expression of the Wnt-effector Tcf7l2, involving the participation of the ubiquitin-proteasome system. Via Tcf7l2 pharmacological inhibition we suggest that Tcf7l2 plays a role in regulating FAPs survival and fate.

Therefore, in this Ph.D. Thesis we studied and proposed that FAPs modulators and signaling governing pathways might be suitable for a novel therapeutic target for the treatment of MD, neurodegenerative diseases, non-malignant fibro-proliferative disorders, and aging.

• Nombre: Osvaldo Contreras Saavedra
• Laboratorio: Diferenciación Celular y Patología
• Mención: Biología Celular y Molecular
• Director Tesis: Enrique Brandan