Administration of AG490 decreases the senescence of umbilical cord-mesenchymal stem cells and promotes the cytotherapeutic effect in liver fibrosis

• Authors: Chenhao Jiang, Sun Yat-Sen University; Huaxin Chen, Sun Yat-Sen University; Yinqian Kang, Sun Yat-Sen University; Xinyi He, Sun Yat-Sen University; Jianyang Huang, Sun Yat-Sen University; Tongyu Lu, Sun Yat-Sen University; Xin Sui, Sun Yat-Sen University; Haitian Chen, Sun Yat-Sen University; Jiaqi Xiao, Sun Yat-Sen University; Jiebin Zhang, Sun Yat-Sen University; Hanwen Zhang, Emory University; Jun Zheng, Sun Yat-Sen University; Yang Yang, Sun Yat-Sen University; Jia Yao, Sun Yat-Sen University; Jianye Cai, Sun Yat-Sen University; Yingcai Zhang, Sun Yat-Sen University
• Journal Title: CELL DEATH DISCOVERY
• Volume: Volume 9, Number 1
• Publisher: SPRINGERNATURE | 2023-07-28, Pages 273-273
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41420-023-01546-3
• Subjects: Health Sciences, Medicine and Surgery; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; CELLULAR SENESCENCE; MECHANISMS; THERAPIES; CIRRHOSIS; DISEASE

Abstract

The therapeutic potential of umbilical cord-mesenchymal stem cell (UC-MSC) transplantation in liver fibrosis has been highlighted. However, the fate of transplanted MSCs in the fibrotic microenvironment remains unclear. In this study, we aim to uncover the fate of transplanted MSCs and develop targeting strategies that could enhance the therapeutic efficacy of MSC therapy in liver fibrosis. We used human UC-MSCs as the study object. For in vitro experiments, we stimulated UC-MSCs with several fibrotic-related factors (Liver fibrotic Factors, LF), including TGFβ, TNFα and IFNγ for downstream investigations. We co-cultured LF-treated UC-MSCs with hepatic stellate cell line LX-2 to assess the anti-fibrotic effect. We showed that upon LF stimulation, UC-MSCs exhibited reduced anti-fibrotic activity and underwent rapid senescence. Pathway analysis showed that JAK/STAT3 signaling was highly activated upon LF stimulation, which significantly elevated senescence-associated secretory phenotype (SASP) and senescence in UC-MSCs and could be reversed by a specific JAK inhibitor AG490. Moreover, using both carbon tetrachloride (CCl4) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induce fibrosis models, we demonstrated that AG490 pretreatment promoted UC-MSCs survival within the fibrotic liver microenvironment and exhibited enhance therapeutic efficacy. Overall, we showed that targeting MSC senescence in vivo through AG490 pretreatment could enhance the anti-fibrotic activities of UC-MSCs.