Abstract
Regeneration relies on coordinated action of multiple cell types to reconstitute the damaged tissue. Here we inactivate the endocytic adaptor protein Numb in skeletal muscle stem cells prior to chronic or severe muscle injury in mice. We observe two types of senescence in regenerating muscle; a transient senescence in non-myogenic cells of control and Numb mutant mice that partly depends on INK4a/ARF activity, and a persistent senescence in myogenic cells lacking Numb. The senescence levels of Numb-deficient muscle is reduced to wild type levels by an anti-oxidant treatment or p53 ablation, resulting in functional rescue of the regenerative potential in Numb mutants. Ex vivo experiments suggest that Numb-deficient senescent cells recruit macrophages to sustain inflammation and drive fibrosis, two hallmarks of the impaired muscle regeneration in Numb mutants. These findings provide insights into previously reported developmental and oncogenic senescence that are also differentially regulated by p53.
Highlights
Regeneration relies on coordinated action of multiple cell types to reconstitute the damaged tissue
Numb is widely expressed in different cell types in the muscle and we observed that this protein is expressed in about 85% of both quiescent and ex vivo activated satellite cells (Supplementary Fig.1a–c)
Sirius Red staining on Tibialis anterior (TA) muscle revealed increased fibrosis in mutants that was accompanied by a slight increase in the number of fibroblast-like (Tcf[4] þ ) cells (Fig. 1f–h)
Summary
Regeneration relies on coordinated action of multiple cell types to reconstitute the damaged tissue. Ex vivo experiments suggest that Numb-deficient senescent cells recruit macrophages to sustain inflammation and drive fibrosis, two hallmarks of the impaired muscle regeneration in Numb mutants These findings provide insights into previously reported developmental and oncogenic senescence that are differentially regulated by p53. The inflammatory response that is mediated through the action of macrophages is necessary to repair damaged tissues Communication between these distinct cell types is crucial during the process of regeneration, as sustained inflammation drives aberrant fibrosis and contributes to pathology[8]. We unveiled two types of senescence during regeneration; a transient senescence in non-myogenic cells in control and Numb mutant mice, which is partially dependent on Ink4A/ARF activity, and a persistent senescence in myogenic cells, exclusively in Numb mutant mice The latter depends on p53 and is rescued by the administration of anti-oxidant. In vivo and ex vivo experiments further showed that Numb mutant-specific senescent cells are responsible for the impaired regeneration phenotype
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
