p16(INK4A)-expressing mesenchymal stromal cells restore the senescence–clearance–regeneration sequence that is impaired in chronic muscle inflammation

BACKGROUND: The therapeutic benefits of mesenchymal stromal cells (MSCs) include treatment of chronic inflammation. However, given the short-lived engraftment of these cells in vivo, their therapeutic efficacy remains mysterious. Transient induction of cellular senescence contributes to activation of immune cells, which promotes clearance of damaged cells during tissue remodelling. This may occur in tissue-resident mesenchymal progenitor cells during regeneration. Elucidation of the role of senescence in tissue-resident mesenchymal progenitor cells during regeneration would provide insight into the profile of therapeutic MSCs for treatment of chronic inflammatory disease. METHODS: We evaluated multipotent mesenchymal progenitor cells, termed fibro/adipogenic progenitors (FAPs), and immune cells in acute muscle injury (AMI) model mice and mice with myosin-induced experimental autoimmune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract. FINDING: FAPs in AMI transiently expressed p16(INK4A) on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16(INK4A) expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16(INK4A) expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16(INK4A)-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells. INTERPRETATION: MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes.