Engineered Heterochronic Parabiosis in 3D Microphysiological System for Identification of Muscle Rejuvenating Factors

Exposure of a young systemic milieu reveals remarkable rejuvenation effects on aged tissues, including skeletal muscle. Although some candidate factors have been reported, the exact underlying mechanisms of putative rejuvenating factors remain elusive, mainly due to the experimental challenges of using in vivo parabiosis. An in vitro parabiosis system is reported here that integrates young‐ and old‐muscle stem cell vascular niche on a 3D microfluidic platform designed to recapitulate key features of native muscle stem cell microenvironment. This 3D micro‐physiological system enables mechanistic studies of cellular dynamics and molecular interactions within the muscle stem cell niche, especially in response to conditional extrinsic stimuli of local and systemic factors. Using engineered parabiosis system, it is demonstrated that vascular endothelial growth factor signaling from endothelial cells and myotubes synergistically contributes to the rejuvenation of the aged muscle stem cell function. Moreover, with the adjustable on‐chip system, both blood transfusion and parabiosis can be mimicked and the time‐varying effects of antigeronic and progeronic factors can be monitored in a single organ or multiorgan systems. The microfluidic system can be utilized as a complementary in vitro microphysiological model to aid the complex in vivo parabiosis studies. This study describes an in vitro muscle parabiosis system that harnesses biochemical and biophysical properties of the muscle stem cell vascular niche and intercirculation of blood‐borne‐factors between young and old muscle microenvironments. The engineered parabiosis provides a minimally invasive system that complements in vivo parabiosis studies and allows identification of pro‐ and anti‐geronic factors.