Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model
Feng Chen1
Zhaodi Che2
Yingxia Liu3
Pingping Luo2
Lu Xiao2
Yali Song2
Cunchuan Wang2
Zhiyong Dong2
Mianhuan Li3
George L.Tipoe4
Min Yang3
Yi Lv5
Hong Zhang6
Fei Wang7
Jia Xiao8
1.Division of Gastroenterology,Seventh Affiliated Hospital of Sun Yat-sen University,Shenzhen,Guangdong,P.R.China;National Clinical Research Center for Infectious Diseases,Second Affiliated Hospital of Southern University of Science and Technology,Shenzhen,Guangdong,P.R.China2.Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery,The First Affiliated Hospital of Jinan University,Guangzhou,Guangdong,P.R.China3.National Clinical Research Center for Infectious Diseases,Second Affiliated Hospital of Southern University of Science and Technology,Shenzhen,Guangdong,P.R.China4.School of Biomedical Sciences,The University of Hong Kong,Hong Kong SAR,P.R.China5.Laboratory of Neuroendocrinology,Fujian Key Laboratory of Developmental and Neurobiology,School of Life Sciences,Fujian Normal University,Fuzhou,Fujian,P.R.China6.Department of Surgery,The Sixth Affiliated Hospital of Jinan University,Jinan University,Dongguan,Guangdong,P.R.China7.Division of Gastroenterology,Seventh Affiliated Hospital of Sun Yat-sen University,Shenzhen,Guangdong,P.R.China8.Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery,The First Affiliated Hospital of Jinan University,Guangzhou,Guangdong,P.R.China;Department of Surgery,The Sixth Affiliated Hospital of Jinan University,Jinan University,Dongguan,Guangdong,P.R.China
摘要：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 re-cipient 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-α/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-γ/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.
机标关键词：mscshumanmousemodelacutechronicco-stimulationfailure
论文发表日期：2024-08-30
在线出版日期：2026-07-17（本平台首次上网日期，不代表文献的发表时间）
页数：13( 373-385 )
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