Hippo pathway activation in aged mesenchymal stem cells contributes to the dysregulation of hepatic inflammation in aged mice

Aging is always accompanied by chronic diseases, including osteoarthritis, fibrosis, type II diabetes, Alzheimer’s disease, cardiovascular disease and cancer and liver diseases. Aging associated diseases probably attribute to longterm chronic inflammation in the aging body, which is called “inflammaging”. Whereas, the mechanism of chronic inflammation in aging body is still obscure. Mesenchymal stem cells (MSCs) exist in all tissues and play critical roles in maintaining tissue homoeostasis. MSCs are capable of local chemotaxis to sites of inflammation and play a powerful role in immune regulation. MSCs are endowed with a potent immune modulation capacity in the inflammatory environment due to their ability to regulate T cell, B cell, dendritic cell, and natural killer cell functions and to promote macrophage polarization to an anti-inflammatory phenotype. Aging of MSCs and tissue specific stem cells (SCs) is involved in various age-related diseases. Whether degeneration of MSCs in the aging body is associated with unbalanced inflammation is still not clear. In this study, we will investigate changes in immune regulatory function of aged MSCs and their impact on enhanced age-related hepatic inflammation. On the other hand, MSCs are also used in clinical trials for the treatment of immune-related diseases, and the functional decline caused by aging limits their clinical application. Thus, this work may also help to build new strategies for improving the clinical efficacy of MSCs. In this study, immunosuppressive properties of aged MSCs was found to be repressed. The impaired immunosuppressive function of aged MSCs is associated with lower expression of the Hippo effector Yes-associated protein 1 (YAP1) and its target gene signal transducer and activator of transcription 1 (STAT1), whose activation could stimulate iNOS expression. YAP1 regulates the transcription of STAT1 through binding with its promoter. We also analyzed the correlation of YAP1 expression in MSCs with the inflammatory status in human liver diseases. The patients with lower expression level of YAP1 in MSCs presented higher inflammation. On the other hand, YAP1 expression was highly positive correlated with STAT1 expression in human MSCs. In conclusion, a novel YAP1/STAT1 axis maintaining immunosuppressive function of MSCs was revealed and impairment of this signal pathway in aged MSCs probably resulted in higher inflammation in aged mice liver.