Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model

Chen, Feng1,2; Che, Zhaodi3,4; Liu, Yingxia2; Luo, Pingping3,4; Xiao, Lu3,4; Song, Yali3,4; Wang, Cunchuan3,4; Dong, Zhiyong3,4; Li, Mianhuan2; Tipoe, George L.5; Yang, Min2; Lv, Yi6; Zhang, Hong7; Wang, Fei1; Xiao, Jia3,4,7

2023-12-22

10.1093/gastro/goae016

GASTROENTEROLOGY REPORT   影响因子和分区

2052-0034

Background Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes.Methods Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-alpha/H2O2. Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4).Results Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro. In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-gamma/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs.Conclusions Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms.

mesenchymal stromal cells acute-on-chronic liver failure Nrf2/DKK1 CKAP4 oxidative stress

SCI

英语

其他

National Natural Science Foundation of China[2016-07]

Gastroenterology & Hepatology

Gastroenterology & Hepatology

WOS:001190149700001

OXFORD UNIV PRESS

Web of Science

1.Sun Yat sen Univ, Affiliated Hosp 7, Div Gastroenterol, 628 Zhenyuan Rd, Shenzhen 518107, Guangdong, Peoples R China
2.Southern Univ Sci & Technol, Natl Clin Res Ctr Infect Dis, Affiliated Hosp 2, Shenzhen, Guangdong, Peoples R China
3.Jinan Univ, Clin Med Res Inst, Affiliated Hosp 1, 613 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China
4.Jinan Univ, Dept Metab & Bariatr Surg, Affiliated Hosp 1, 613 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China
5.Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China
6.Fujian Normal Univ, Sch Life Sci, Lab Neuroendocrinol, Fujian Key Lab Dev & Neurobiol, Fuzhou, Fujian, Peoples R China
7.Jinan Univ, Affiliated Hosp 6, Dept Surg, Dongguan, Guangdong, Peoples R China

Chen, Feng,Che, Zhaodi,Liu, Yingxia,et al. Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model[J]. GASTROENTEROLOGY REPORT,2023,12.

Chen, Feng.,Che, Zhaodi.,Liu, Yingxia.,Luo, Pingping.,Xiao, Lu.,...&Xiao, Jia.(2023).Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model.GASTROENTEROLOGY REPORT,12.

Chen, Feng,et al."Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model".GASTROENTEROLOGY REPORT 12(2023).