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 tr...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-a/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-c/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.展开更多
基金funded by grants from the National Natural Science Foundation of China[nos 82122009,81970515,82170605,and 81873573]the Guangdong Natural Science Funds for Distinguished Young Scholar[no.2019B151502013]the Guangdong Basic and Applied Research Foundation[no.2021B1515120069].
文摘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-a/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-c/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.
