On April 1st, 2019, a research article entitled “Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis” was published in PLOS Biology by scientists from the Institute of Biophysics of the Chinese Academy of Sciences, Peking University, and the Institute of Zoology of the Chinese Academy of Sciences. They found a geroprotective role of YAP-FOXD1 axis in rejuvenating human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis symptoms in mouse models, suggesting novel targets for combating aging-associated disorders.

Cellular senescence and stem cell exhaustion are hallmarks and drivers of various aging-associated disorders including osteoarthritis, one of the most common degenerative diseases whose incidence increases with age. It emerges from the disruption of the superficial zone of cartilage where MSCs and chondrocyte progenitor cells reside. Therefore, a comprehensive understanding of the underlying mechanisms of MSC senescence will likely reveal novel therapeutic targets for osteoarthritis.

YAP, an effector of Hippo signaling, plays important roles in development and cell fate decision. The researchers generated YAP knockout hMSCs by combing CRISPR/Cas9-mediated gene-editing in human embryonic stem cells (hESCs) and directed differentiation techniques, and observed premature cellular senescent phenotypes in these cells. Mechanistically, YAP cooperated with TEA domain transcriptional factor (TEAD) to activate the expression of forkhead box D1 (FOXD1), a geroprotective protein. YAP and FOXD1 were both down-regulated in aged hMSCs, whereas overexpression of either YAP or FOXD1 rejuvenated aged hMSCs. More importantly, intra-articular administration of lentiviral vector encoding YAP or FOXD1 sufficiently reduced the percentage of senescent cells, inhibited articular inflammation, and cartilage erosion, thereby ameliorating the pathological symptoms of osteoarthritis in mice. These findings not only define a critical role of YAP-FOXD1 axis in regulating hMSC aging but also demonstrate the therapeutic potential of targeting YAP-FOXD1 axis to relieve osteoarthritis.

Figure. Gene therapy via lentiviral introduction of YAP or FOXD1 alleviates osteoarthritis

(Imaged by Dr. Liu Guanghui’s group)

Taken together, Guang-Hui Liu and his colleagues endow YAP-FOXD1 as a novel aging-associated regulatory axis and provide a proof-of-concept that gene therapy via the introduction of single geroprotective factors aiming at rejuvenating senescent cells may represent a new avenue to treating aging-associated disorders in the future.

Article link: https://journals.plos.org/plosbiology/article/authors?id=10.1371/journal.pbio.3000201