Fibro-adipogenic progenitors enhance functional and structural properties of human 3D tissue engineered skeletal muscles

Human skeletal muscle models often lack important supportive cell types. Here we developed a co-culture three-dimensional tissue engineered skeletal muscle (3D-TESM) model by combining myogenic progenitors (MPs) with genetically-matched immortalized fibro-adipogenic progenitors (iFAPs). FAPs play a crucial physiological role in myogenesis, tissue remodeling and extracellular matrix (ECM) formation. We demonstrate that co-culture 3D-TESMs effectively recapitulate these processes under controlled conditions, thereby enhancing contractile force, muscle tissue integrity and longevity, as well as improving ECM deposition compared to MP-only 3D-TESMs. Moreover, using pro-fibrotic and pro-adipogenic cell culture compositions we were able to mimic pathological features typically observed in muscular dystrophies: excessive ECM production and the formation of fatty infiltrations. This study provides an advanced skeletal muscle model, with enhanced functional and structural properties, capable of recapitulating pathophysiological processes that require FAPs.