In a study published in PLOS Biology on April 1, scientists from the Institute of Biophysics of Chinese Academy of Sciences (CAS), Peking University, and the Institute of Zoology of CAS, reported their discovery of 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. Osteoarthritis emerges from the disruption of the superficial zone of cartilage where MSCs and chondrocyte progenitor cells reside.
YAP, an effector of Hippo signaling, plays important roles in development and cell fate decision. By combing CRISPR/Cas9-mediated gene-editing in hESCs and directed differentiation techniques, scientists generated YAP knock out human embryonic stem cells (hESCs). They 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.
Besides, 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 defined a critical role of YAP-FOXD1 axis in regulating hMSC aging, but also demonstrated the therapeutic potential of targeting YAP-FOXD1 axis to relieve osteoarthritis.
This study endows YAP-FOXD1 as a novel aging-associated regulatory axis. It also provides 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.
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