Upregulation of YAP or FOXD1 Reduces Cellular Senescence and Osteoarthritis in Mice

Senescent cells are now a prominent target for the development of therapies to treat aging and age-related diseases. Senescent cells accumulate with age, and are responsible for a sizable amount of the chronic inflammation that accompanies old age - as well as fibrosis, compromised regeneration, and a laundry list of other issues. While the dominant approach is selective destruction of these cells, which appears to produce rejuvenation robustly and effectively in mice, a fair number of research groups are interested in finding ways to prevent cells from becoming senescent in the first place. The investigation here into cellular senescence and osteoarthritis is an example of the type.

I'm not convinced that this is as useful a path forward. Firstly it means constantly taking the treatment over decades, rather than once every so often, as needed. Secondly, cells become senescent for a reason, usually some form of DNA damage or environmental stress. Preventing senescence may result in a higher risk of cancer or other problems in tissue due to cells that should in fact be removed from the picture. That may still be better than the alternative of more rather than fewer senescent cells, as was the case in the short term for the mice in this study, but it doesn't compare favorably with destroying these errant cells.

Mesenchymal stem cells (MSCs) are widely distributed in adult tissues and are involved in tissue repair and homeostatic maintenance. Over time, MSCs exhibit an age-associated decline in their number and function, namely, MSC senescence, which may be implicated in the loss of tissue homeostatic maintenance and leads to organ failure and degenerative diseases. Therefore, an understanding of the mechanisms underlying MSC senescence will likely reveal novel therapeutic targets for ameliorating degenerative diseases.

Osteoarthritis is a prevalent aging-associated disorder that is characterized by the progressive deterioration of articular cartilage. Previous reports have demonstrated that cells isolated from mouse and human articular cartilage express MSC markers and characteristics. Cell death induced by oxidative stress or wound occurs primarily at the surface zone of cartilage. When such cell death is inhibited by chemicals, cartilage disorganization and matrix loss are greatly reduced. Therefore, MSCs or chondrocyte progenitor cells residing in cartilage may be a critical target for the prevention of osteoarthritis. Although the transplantation of ex vivo cultures of MSCs into the osteoarthritic joint has been shown to improve the symptoms, the rejuvenation of endogenous senescent MSCs may also be a therapeutic option for osteoarthritis.

Senescent mesenchymal stem cells (MSCs) residing in the joint cartilage may be a critical target for the prevention of osteoarthritis; however, the key regulators of MSC senescence are little known, and targeting aging regulatory genes for the treatment of osteoarthritis has not yet been reported. Here, we show that Yes-associated protein (YAP), a major effector of Hippo signaling, represses human mesenchymal stem cell senescence through transcriptional up-regulation of forkhead box D1 (FOXD1). Lentiviral gene transfer of YAP or FOXD1 can rejuvenate aged hMSCs and ameliorate osteoarthritis symptoms in mouse models. We propose that the YAP-FOXD1 axis is a novel target for combating aging-associated diseases.

Link: https://doi.org/10.1371/journal.pbio.3000201

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