p16INK4A-Expressing Mesenchymal Stromal Cells Restore the Senescence-Clearance-Regeneration Sequence that is Impaired in Chronic Muscle Inflammation

The therapeutic benefits of mesenchymal stromal cells (MSCs) are well documented, but given the short-lived engraftment of these cells in vivo, currently no plausible hypotheses explain their therapeutic efficacy. Transient induction of cell senescence contributes to cell clearance followed by tissue remodeling. Here, we show that p16INK4A expression by therapeutic MSCs was induced by placental extracts in culture. Cellular senescence occurs during the natural maturation program of the placenta. Treatment of chronic inflammatory myopathy (CIM) mice with p16INK4Aexpressing MSCs promoted tissue remodeling by transiently increasing the abundance of engrafted MSCs, induced cellular senescence in innate fibro/adipogenic progenitors (FAPs), and recruited phagocytic immune cells. This phenomenon was similar to the endogenous regeneration process after acute damage to skeletal muscle. Our findings reveal that MSCs may exert their effect by remodeling the chronic inflammatory environment via senescence-related regenerative processes. Funding Statement: This work supported by Medical Research Grant in Sapporo Medical University and JSPS KAKENHI Grant Number JP16K16430 Declaration of Interests: The authors declare no competing interests associated with this manuscript. Ethics Approval Statement: All animal protocols were approved by the Committee of the Animal Experimentation Center of the Sapporo Medical University School of Medicine. Collection of samples and their use for research purposes were approved by our institutional review board