p16INK4A-expressing mesenchymal stromal cells restore the senescence–clearance–regeneration sequence that is impaired in chronic muscle inflammation

Abstract

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.

Reduced stem cell aging in exercised human skeletal muscle is enhanced by ginsenoside Rg1

“…Another novel finding of the study is a very large correlation (r = 0.84) between p16 INK4a and MPO expression in human muscle tissues. This result supports the notion that cellular senescence in normally tissues attracts neutrophil infiltration to elevate inflammation, suggested by animal and in vitro studies [16,24]. MPO is expressed specifically in neutrophils [17] which infiltrates in muscle tissue during phagocytic phase of inflammation [25].…”

Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges

“…Tumor suppressor genes p16 and p21 play an important role in monitoring the normal integrity of DNA. Senescence of MSCs has been shown to be reversed by ablation of p16 or p21 (Chikenji, 2019). The protein level of p16 or p21 may indicate the parallel level of MSC senescence.…”

Loss of p16: A Bouncer of the Immunological Surveillance?

“…These pieces of evidence suggest that low CDKN2A expression both impacts the number and the activity of the intratumoral immune cells. Moreover, suppression of CDKN2A in mesenchymal stromal cells has been shown to decrease CD11b+ Gr-1 hi neutrophils, CD11b+ Gr1 low monocytes and CD45-CD31-Integrinα7+ satellite cells in a model of chronic inflammatory myopathy [ 17 ]. Although all those investigations are based on correlative analysis, these data may indicate that CDKN2A is necessary for regulation of the physiological immune response upon different inflammatory events.…”

“…On one hand, loss of p16 is a common feature of cancer that causes an increase in the proliferative capacity of the cell [ 12 ]; on the other hand, upregulation of p16 is a hallmark of senescence that contributes to the characteristic state of cell cycle arrest [ 13 ]. Interestingly, recent publications demonstrate that suppression of p16 correlates with decreased activity of immune cells [ 14 , 15 , 16 , 17 ], and our recent publication shows that p16 suppression decreases expression of the SASP [ 18 ]. Altogether these data suggest that p16 may have a, yet unknown, role in the regulation of tumor immunity that might have important implications in the treatment of cancers with low or null p16 expression.…”