Project title: Modulation of fibrogenesis and adipogenesis during skeletal muscle regeneration

Type of rotation: M2 (6 months)

Supervisor: Françoise HELMBACHER

Concept and Objectives

Our team is interested in the mechanisms of muscle development and regeneration, dysfunction of which underlie the pathological mechanisms at the root of muscle pathologies. We explore the cross-talks between myogenic cells and connective tissue that underlie myogenic growth, with a focus on muscle-resident cells called fibro-adipogenic progenitors (FAPs). Whereas in healthy muscle, FAPs act as a support cells for myogenic repair after tissue lesion, they are at the origin of intramuscular fibro-adipose infiltration in diseased muscle (muscle dystrophy, diabetes, aging). Using a method involving AAV vectors and CRISPR/dCas9 to modulate gene expression in FAPs, we aim to uncover the mechanisms that ensure FAP homeostasis during skeletal muscle regeneration, and to identify means of blocking fibro-adipose development in muscle pathologies. Our approach is designed to visualize transduced cells with bioluminescent reporters, and allows monitoring expansion and regression of the FAP lineage during muscle repair by non-invasive longitudinal imaging.

During this master project (M2) the student will apply the above method to obtain proof of principle that targeting selected candidate genes can efficiently induce or suppress intramuscular adipose tissue formation. During this project the student will use standard methods of histology and fluorescence microscopy and will start using bioluminescence imaging on living mice.

References

• Helmbacher F, Stricker S. Tissue cross talks governing limb muscle development and regeneration. Semin Cell Dev Biol. (2020) Jun 6:S1084-9521(19)30131-4. doi: 10.1016/j.semcdb.2020.05.005. Review.
• Helmbacher F. Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis. PLoS Biol. (2018) May 16;16(5):e2004734. doi: 10.1371/journal.pbio.2004734
• Helmbacher Astrocyte-intrinsic and extrinsic Fat1 activities regulate astrocyte development and angiogenesis in the retina. Development, (2022)Jan 15;149(2):dev192047
• Caruso N, Herberth B, Bartoli M, Puppo F, Dumonceaux J, Zimmermann A, Denadai S, Lebossé M, Roche S, Geng L, Magdinier F, Attarian S, Bernard R, Maina F, Levy N, Helmbacher F. Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy. PLoS Genet. (2013) Jun;9(6):e1003550.
• Puppo F., Dionnet E., Gaillard MC., Gaildrat P., et al…., Magdinier F., Krahn, M., Helmbacher, F., Bartoli, M, and Levy, N. Identification of variants in the 4q35 gene FAT1 in patients with a Facioscapulohumeral dystrophy (FSHD)-like phenotype. Human Mutation. (2015) Apr;36(4):443-53. DOI: 10.1002/humu.22760