In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche

• Published in: Nature communications Vol. 12; no. 1; p. 3094
• Main Authors: Wang, Chao, Rabadan Ros, Ruben, Martinez-Redondo, Paloma, Ma, Zaijun, Shi, Lei, Xue, Yuan, Guillen-Guillen, Isabel, Huang, Ling, Hishida, Tomoaki, Liao, Hsin-Kai, Nuñez Delicado, Estrella, Rodriguez Esteban, Concepcion, Guillen-Garcia, Pedro, Reddy, Pradeep, Izpisua Belmonte, Juan Carlos
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-05-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 631/136/7/1640; 631/1647; 631/532/2439; 631/80; 692/308/2171; Aging; c-Myc protein; Cell activation; Gene expression; Humanities and Social Sciences; KLF4 protein; Microenvironments; multidisciplinary; Muscles; Myc protein; Regeneration; Satellite cells; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Tissue engineering; Tissues; Wnt protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23353-z

Short-term, systemic expression of the Yamanaka reprogramming factors (
Oct-3/4
,
Sox2
,
Klf4
and
c-Myc
[OSKM]) has been shown to rejuvenate aging cells and promote tissue regeneration in vivo. However, the mechanisms by which OSKM promotes tissue regeneration are unknown. In this work, we focus on a specific tissue and demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice. In contrast, expressing OSKM directly in SCs does not improve muscle regeneration. Mechanistically, expressing OSKM in myofibers regulates the expression of genes important for the SC microenvironment, including upregulation of p21, which in turn downregulates
Wnt4
. This is critical because Wnt4 is secreted by myofibers to maintain SC quiescence. Thus, short-term induction of the Yamanaka factors in myofibers may promote tissue regeneration by modifying the stem cell niche.
Short term systemic expression of the reprogramming factors Oct-3/4, Sox2, Klf4, c-Myc (OSKM) rejuvenates aging cells and promotes tissue regeneration. Here the authors show that myofiber-specific expression of OSKM accelerates muscle regeneration by reducing secretion of muscle stem cell quiescence promoting Wnt4.