Telomeres and Cellular Senescence in Tissue Repair and Cell Plasticity

SCs secrete numerous bioreactive molecules, a phenomenon called the Senescence-Associated Secretory Phenotype (SASP). SASP factors have been shown to exert various effects on cells, such as stabilizing the senescence growth arrest in an autocrine manner, as well as regulating tissue patterning, inducing cell plasticity, stemness, transdifferentiation, and immune cell recruitment in a paracrine manner. While SASP factors have been demonstrated to promote tissue repair, details about how they accomplish this remain unclear. Our data revealed that SASP factors secreted from senescent fibroblasts, including TGFb1, can cause telomere dysfunction in neighboring fibroblasts, causing them to transdifferentiate into myofibroblasts, a contractile cell type that is critical for wound healing and tissue repair. Significantly, our data further demonstrated that telomere dysfunction was required for myofibroblasts transdifferentiation, a surprising finding, as telomere dysfunction is an event thought to exclusively lead to cellular senescence (Figure 3; Razdan et al., 2018, Aging Cell). Current studies are characterizing the diverse and pleiotropic effects of the SASP. We are testing the hypothesis that synthesis and secretion of SASP factors is a temporally evolving and dynamic process, beginning with cytokines that promote cell plasticity and facilitate reprogramming, followed by those that induce transdifferentiation, and ending with factors that recruit immune cells and eventually exert damaging effects on surrounding cells and tissue. Our study will ultimately enable us to exploit the beneficial properties of the early SASP for therapeutic application in regenerative medicine and age-associated disorders, as well as suppress the damaging effects of the late SASP to improve health and healthspan in humans.