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

Chenhao Jiang; Huaxin Chen; Yinqian Kang; Xinyi He; Jianyang Huang; Tongyu Lu; Xin Sui; Haitian Chen; Jiaqi Xiao; Jiebin Zhang; Hanwen Zhang; Jun Zheng; Yang Yang; Jia Yao; Jianye Cai; Yingcai Zhang

doi:10.1038/s41420-023-01546-3

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

Cell Death Discov. 2023 Jul 28;9(1):273. doi: 10.1038/s41420-023-01546-3.

Authors

Chenhao Jiang^#^{1

2}, Huaxin Chen^#³, Yinqian Kang^#⁴, Xinyi He^#⁵, Jianyang Huang⁵, Tongyu Lu^{1

2}, Xin Sui⁶, Haitian Chen^{1

2}, Jiaqi Xiao^{1

2}, Jiebin Zhang^{1

2}, Hanwen Zhang⁷, Jun Zheng^{1

2}, Yang Yang^{1

2}, Jia Yao^{8

9}, Jianye Cai^{10

11}, Yingcai Zhang^{12

13}

Affiliations

¹ Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China.
³ Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁴ Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
⁵ Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
⁶ Surgical ICU, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
⁷ Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30309, USA.
⁸ Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. yaojia6@mail.sysu.edu.cn.
⁹ Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China. yaojia6@mail.sysu.edu.cn.
¹⁰ Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. caijy23@mail.sysu.edu.cn.
¹¹ Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China. caijy23@mail.sysu.edu.cn.
¹² Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. zhangyc3@mail.sysu.edu.cn.
¹³ Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China. zhangyc3@mail.sysu.edu.cn.

^# Contributed equally.

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.

Abstract

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