Evidence for Cellular Senescence to Contribute to Retinal Degeneration
Forms of retinal degeneration are commonplace in later life, leading to progressive and presently irreversible blindness - though there are promising human trial results emerging from the tissue engineering community of late. The accumulation of senescent cells is a feature of aging found in all tissues. These errant cells should self-destruct or be destroyed by the immune system, but enough survive to linger and cause problems. They secrete an inflammatory mix of signals that disrupts normal tissue structure and function, and their presence is one of the root causes of aging. Thus it is not surprising to find evidence for senescent cells to contribute to retinal degeneration, such as that presented here.
It is good news for patients, and everyone else, whenever cellular senescence is associated with the progression of yet another age-related condition. Low-cost senolytic drugs capable of removing a significant fraction of senescent cells already exist, and numerous companies are working on the commercial development of further and better options. To the degree that we can all access senolytic treatments, and to the degree that those treatments are efficient in removing unwanted senescent cells, then we will age more slowly and the onset of age-related diseases will be postponed.
Regenerative medicine approaches based on mesenchymal stem cells (MSCs) are being investigated to treat several aging-associated diseases, including age-related macular degeneration (AMD). Loss of retinal pigment epithelium (RPE) cells occurs early in AMD, and their transplant has the potential to slow disease progression. The human RPE contains a subpopulation of cells - adult RPE stem cells (RPESCs) - that are capable of self-renewal and of differentiating into RPE cells in vitro. However, age-related MSC changes involve loss of function and acquisition of a senescence-associated secretory phenotype (SASP), which can contribute to the maintenance of a chronic state of low-grade inflammation in tissues and organs.
In a previous study we isolated, characterized, and differentiated RPESCs. Here, we induced replicative senescence in RPESCs and tested their acquisition of the senescence phenotype and the SASP as well as the differentiation ability of young and senescent RPESCs. Senescent RPESCs showed a significantly reduced proliferation ability, high senescence-associated β-galactosidase activity, and SASP acquisition. RPE-specific genes were downregulated and p21 and p53 protein expression was upregulated. Altogether, the present findings indicate that RPESCs can undergo replicative senescence, which affects their proliferation and differentiation ability. In addition, senescent RPESCs acquired the SASP, which probably compounds the inflammatory RPE microenvironment during AMD development and progression.