Cellular Senescence in Acute and Chronic Wound Repair

Abstract

Cellular senescence, once thought an artifact of in vitro culture or passive outcome of aging, has emerged as fundamental to tissue development and function. The senescence mechanism importantly halts cell cycle progression to protect against tumor formation, while transiently present senescent cells produce a complex secretome (or SASP) of inflammatory mediators, proteases, and growth factors that guide developmental remodeling and tissue regeneration. Transiently present senescence is important for skin repair, where it accelerates extracellular matrix formation, limits fibrosis, promotes reepithelialization, and modulates inflammation. Unfortunately, advanced age and diabetes drive pathological accumulation of senescent cells in chronic wounds, which is perpetuated by a proinflammatory SASP, advanced glycation end-products, and oxidative damage. Although the biology of wound senescence remains incompletely understood, drugs that selectively target senescent cells are showing promise in clinical trials for diverse pathological conditions. It may not be long before senescence-targeted therapies will be available for the management, or perhaps even prevention, of chronic wounds.

Figure 1.

Characteristics of senescent cells. Senescent cells undergo cell cycle arrest and feature DNA alterations such as senescence-associated heterochromatin foci (SAHF), DNA-SCARS, and markers of DNA damage. A disrupted nuclear envelope is accompanied by reduction in the structural nuclear envelope protein, lamin B1, and the release of chromatin into the cytoplasm. Senescent cells show mitochondrial dysfunction, with increased production of reactive oxygen species (ROS) and up-regulation of prosurvival (antiapoptotic) pathways. Morphologically, senescent cells appear flattened and elongated with enlargement of lysosomes, enabling detection by senescence-associated β-galactosidase (SA-βGAL) and lipofuscin. In addition, senescent cells feature a senescence-associated secretory phenotype (SASP) containing proteases, cytokines, matrix metalloproteinases (MMPs), and extracellular vesicles (ECVs).

Figure 2.

Diverse roles for senescence throughout life. Transiently present (short-term) senescence is required during development, tissue regeneration, and wound repair. Here, senescent cells produce a beneficial senescence-associated secretory phenotype (SASP) that guides developmental patterning and tissue restoration following injury. Effective clearance of senescent cells during these processes prevents chronicity. By contrast, chronological aging leads to accumulation of cellular stress, which drives senescence. Chronic senescence is exacerbated by defective clearance mechanisms and unrestrained inflammation, leading to widespread tissue damage and increased risk of pathology.

Figure 3.

Senescence in acute versus chronic wound healing. In acute wounds, transiently present senescent cells appear during late-stage healing, producing a senescence-associated secretory phenotype (SASP) that aids extracellular matrix (ECM) deposition but prevents tissue fibrosis. Senescent cells are then cleared by the immune system, allowing full tissue resolution. During aging and diabetes, advanced glycation end products (AGEs) and sterile inflammation promote the accumulation of senescent cells. Following injury, these resident senescent cells contribute to a proinflammatory environment that perpetuates senescence, causes tissue breakdown, and prevents healing. Senescence (and inflammation) can also be exacerbated by chronic wound infection. (AI Mφs) Anti-inflammatory macrophages, (PI Mφs) proinflammatory macrophages.