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

Chao Wang, Ruben Rabadan Ros, Paloma Martinez-Redondo, Zaijun Ma, Lei Shi, Yuan Xue, Isabel Guillen-Guillen, Ling Huang, Tomoaki Hishida, Hsin-Kai Liao, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Pedro Guillen-Garcia, Pradeep Reddy and Juan Carlos Izpisua Belmonte ()
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Chao Wang: Gene Expression Laboratory, Salk Institute for Biological Studies
Ruben Rabadan Ros: Gene Expression Laboratory, Salk Institute for Biological Studies
Paloma Martinez-Redondo: Gene Expression Laboratory, Salk Institute for Biological Studies
Zaijun Ma: Gene Expression Laboratory, Salk Institute for Biological Studies
Lei Shi: Gene Expression Laboratory, Salk Institute for Biological Studies
Yuan Xue: Gene Expression Laboratory, Salk Institute for Biological Studies
Isabel Guillen-Guillen: Gene Expression Laboratory, Salk Institute for Biological Studies
Ling Huang: Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies
Tomoaki Hishida: Gene Expression Laboratory, Salk Institute for Biological Studies
Hsin-Kai Liao: Gene Expression Laboratory, Salk Institute for Biological Studies
Estrella Nuñez Delicado: Universidad Católica San Antonio de Murcia (UCAM), Campus de los Jerónimos
Concepcion Rodriguez Esteban: Gene Expression Laboratory, Salk Institute for Biological Studies
Pedro Guillen-Garcia: Department of Traumatology and Research Unit, Clinica CEMTRO
Pradeep Reddy: Gene Expression Laboratory, Salk Institute for Biological Studies
Juan Carlos Izpisua Belmonte: Gene Expression Laboratory, Salk Institute for Biological Studies

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23353-z

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