3D Muscle-Tendon Unit modelling for unravelling tissue crosstalk in muscular dystrophies and aging (3D-MTU)

The extracellular matrix (ECM) is an intricate network that play key functions in regulating critical cell processes such as proliferation, adhesion, migration, survival, polarity and differentiation. This is particularly relevant for the muscle-tendon unit (MTU), which regulates motor function downstream a plethora of environmental chemical and mechanical signals. The musculoskeletal system is characterized by a high degree of heterogeneity in terms of cell population, cell density and ECM physical and mechanical properties. ECM plays a pivotal role for the correct assembly of the MTU and the proper organization of the myotendinous junctions (MTJs). Indeed, the enormous mechanical stress at the MTJ sites and the relative risky rupture at the junctional sarcolemma level are sensed by membrane receptors and transduced via mechanosignaling, and subsequently counteracted by an increased and finely regulated expression of cytoskeletal and ECM proteins, such as dystrophin, laminin and collagen VI (COL6). Not surprisingly, the MTU is clearly affected in several diseases. Muscular dystrophies (MDs) and aging-related tendinopathies are characterized by a dramatic and irreversible ECM remodeling, which severely affects the structure and function of the MTU.
We want to investigate the influence of disease-related ECM changes on the function of myogenic and tendon cells innovative 3D in vitro models. Therefore, we propose to investigate the influence of pathological muscle conditions affecting tendon counterpart, and vice versa, by focusing on MDs involving the disruption of muscle ECM-cytoskeletal axis and on aging-related tendinopathies.
Moreover, we want to perform studies on mechanosignaling from the ECM to the nucleus and vice versa, by focusing in particular on the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. We use 3D MTJ culture model of healthy and diseased muscle and tendon obtained from human derived myogenic progenitor cells combined with tenocytes from healthy and pathological conditions, in order to reconstruct MTJs. We want to investigate cellular pathways linking changes in ECM and/or mechanical strain to LINC modulation, with focus on the PI3K/Akt/mTOR pathway and to evaluate changes in nuclear shape and nuclear lamina composition in response to mechanical or TGFbeta-dependent chemical stimulation.

Grants

PRIN2017

Research Group

Vittoria Cenni

Patrizia Sabatelli

Elisabetta Mattioli

Collaborations

Università degli Studi di Bologna

Università di Padova

Università TOR VERGATA

Università di Milano