Senescence Associated MCP 1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells.
AIMS Cellular senescence and its secretory phenotype (senescence associated secretory phenotype [SASP] develop after long term expansion of mesenchymal stromal cells (MSCs) Further investigation of this phenotype is required to improve the therapeutic efficacy of MSC based cell therapies. In this study, we show that positive feedback between SASP and inherent senescence processes plays a crucial role in the senescence of umbilical cord blood derived MSCs (UCB MSCs) RESULTS We found that monocyte chemoattractant protein 1 (MCP 1) was secreted as a dominant component of the SASP during expansion of UCB MSCs and reinforced senescence via its cognate receptor chemokine (c c motif) receptor 2 (CCR2) by activating the ROS p38 MAPK p53/p21 signaling cascade in both an autocrine and paracrine manner. The activated p53 in turn increased MCP 1 secretion, completing a feed forward loop that triggered the senescence program in UCB MSCs. Accordingly, knockdown of CCR2 in UCB MSCs significantly improved their therapeutic ability to alleviate airway inflammation in an experimental allergic asthma model. Moreover, BMI1, a polycomb protein, repressed the expression of MCP 1 by binding to its regulatory elements. The reduction in BMI1 levels during UCB MSC senescence altered the epigenetic status of MCP 1, including the loss of H2AK119Ub, and resulted in derepression of MCP 1. INNOVATION Our results provide the first evidence supporting the existence of the SASP as a causative contributor to UCB MSC senescence and reveal a so far unappreciated link between epigenetic regulation and SASP for maintaining a stable senescent phenotype. CONCLUSION Senescence of UCB MSCs is orchestrated by MCP 1, which is secreted as a major component of the SASP and is epigenetically regulated by BMI1.
Antioxidants redox signaling