Cellular senescence-from solid organs to vascularized composite allotransplants

Vascularized composite allotransplantation (VCA) has emerged as a novel therapy approach to restore form and function in patients with severe tissue defects of the face, hand, and abdominal wall, among other anatomical regions. The composite allografts comprise different tissues such as skin, muscle, or bone. Clinical data demonstrate promising mid- and long-term outcomes following VCA surgery, but our understanding of the cellular interactions and molecular pathways in VCA surgery is oftentimes deduced from solid organ transplantation (SOT). In SOT, the concept of cellular senescence has grown increasingly popular which is characterized by a permanent cellular proliferation arrest in response to endogenous and exogenous stimuli. Senescent cells, through the release of mitochondrial DNA and secretion of proinflammatory proteins, can amplify the immunogenicity of transplants, hindering graft acceptance and longevity. This understanding has paved the way for novel interventions, including the use of senolytics-agents that selectively eliminate senescent cells-to modulate immune responses and mediate immunotolerance. There is a body of evidence that underlines the therapeutic potential of senescence to improve SOT outcomes; however, the relevance of senescence to VCA outcomes remains elusive. In this review, we aim to summarize the current literature on senescence in different solid organ transplants and outline the potential impact of senescence on VCA outcomes. This knowledge may help providers develop a broader understanding of the cellular and molecular landscape in VCA to develop targeted therapies and advance VCA patient care.