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

Chao Wang,Lei Shi,Juan Carlos Izpisua Belmonte,Pedro Guillen-Garcia,Pradeep Reddy,Ling Huang,Estrella Nuñez Delicado,Yuan Xue,Isabel Guillen-Guillen,Tomoaki Hishida,Zaijun Ma,Ruben Rabadan Ros,Concepcion Rodriguez Esteban,Hsin-Kai Liao,Paloma Martinez-Redondo

doi:10.1038/s41467-021-23353-z

Abstract

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.

Highlights

Short-term, systemic expression of the Yamanaka reprogramming factors (Oct-3/4, Sox[2], Klf[4] and c-Myc [OSKM]) has been shown to rejuvenate aging cells and promote tissue regeneration in vivo
We have shown that partial reprogramming promotes skeletal muscle regeneration in 12-month-old mice[8], but these studies were performed by expressing OSKM systemically[8]
The expression of Oct[4], Sox[2], and cMyc was 4-fold higher in Cre+ extensor digitorum longus (EDL) muscles compared with Cre+ SOL muscles (Fig. 1c, d)

Summary

Introduction

Short-term, systemic expression of the Yamanaka reprogramming factors (Oct-3/4, Sox[2], Klf[4] and c-Myc [OSKM]) has been shown to rejuvenate aging cells and promote tissue regeneration in vivo. Besides amelioration of cellular aging hallmarks, reprogramming factors promote tissue regeneration in aged mice[8,10] It is unknown whether OSKM-improved regeneration is solely a result of its rejuvenating effect. We have shown that partial reprogramming promotes skeletal muscle regeneration in 12-month-old mice[8], but these studies were performed by expressing OSKM systemically (i.e., in all cell types)[8] It is unclear whether intrinsic or niche-specific factors contributed to the observed improvement in muscle regeneration. Our data shows that myofiber-specific OSKM induction accelerates muscle regeneration through downregulating the myofiber-secreted niche factor, Wnt[4], to induce the activation and proliferation of SCs. In contrast, SC-specific OSKM induction does not improve muscle regeneration in young mice. We conclude that partial reprogramming via OSKM can remodel the SC niche to induce SC activation and proliferation and accelerate muscle regeneration

Methods

Results

Conclusion