Intervention with metabolites emulating endogenous cell transitions accelerates muscle regeneration in young and aged mice
Reyna Hernández‐Benítez, Chao Wang, Lei Shi, Yasuo Ouchi, Cuiqing Zhong, Tomoaki Hishida, Hsin‐Kai Liao, Eric A. Magill, Sebastian Memczak, Rupa Devi Soligalla, Chiara Fresia, Fumiyuki Hatanaka, Verónica Lamas, Isabel Guillén, Sanjeeb Kumar Sahu, Mako Yamamoto, Yanjiao Shao, Alain Aguirre-Vázquez, Estrella Núñez‐Delicado, Pedro Guillén, Concepción Rodrı́guez Esteban, Jing Qu, Pradeep Reddy, Steve Horvath, Guang‐Hui Liu, Pierre J. Magistretti, Juan Carlos Izpisúa Belmonte
Abstract
Tissue regeneration following an injury requires dynamic cell-state transitions that allow for establishing the cell identities required for the restoration of tissue homeostasis and function. Here, we present a biochemical intervention that induces an intermediate cell state mirroring a transition identified during normal differentiation of myoblasts and other multipotent and pluripotent cells to mature cells. When applied in somatic differentiated cells, the intervention, composed of one-carbon metabolites, reduces some dedifferentiation markers without losing the lineage identity, thus inducing limited reprogramming into a more flexible cell state. Moreover, the intervention enabled accelerated repair after muscle injury in young and aged mice. Overall, our study uncovers a conserved biochemical transitional phase that enhances cellular plasticity in vivo and hints at potential and scalable biochemical interventions of use in regenerative medicine and rejuvenation interventions that may be more tractable than genetic ones.