Hepatocyte growth factor mediates a novel form of hepatic stem/progenitor cell-induced tolerance in a rat xenogeneic liver rejection model

Chen, Quanyu; You, Yu; Zhang, Yujun; Zhang, Hongyu; Bai, Lianhua

doi:10.1016/j.intimp.2020.107180

Cited by 6 publications

(12 citation statements)

References 52 publications

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“…FK506 may act on Tregs, either CD4 + Tregs (69, 70) or CD8 + CD45RC -Tregs (71), rather than directly acting on aCD8 + T cells. The finding in the present study that FK506 has a more potent effect in regulating CD4 + /CD25 + /FoxP3 + Tregs than cHGF/HGF (Figure 4) may explain the mechanisms, although HGF has also been suggested to play a role in tolerance in Treg regulation after LTx (6,7,63,72).…”

Section: Discussionmentioning

confidence: 54%

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Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance

et al. 2023

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Allostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (FK506), the most commonly used immunosuppressant (IS) in the clinic, allows tolerance induction, its use is limited because its target immune cells are unknown and it is associated with increased incidences of malignancy, infection, and nephrotoxicity, which substantially impact long-term liver transplantation (LTx) outcomes. The dark agouti (DA)-to-Lewis rat LTx model is a well-known ARJ model and was hence chosen for the present study. We show that both hepatocyte growth factor (HGF) (cHGF, containing the main form of promoting HGF production) and recombinant HGF (h-rHGF) exert immunoregulatory effects mainly on allogeneic aCD8+ T cell suppression through FAS-mediated apoptotic pathways by inhibiting cMet to FAS antagonism and Fas trimerization, leading to acute tolerance induction. We also showed that such inhibition can be abrogated by treatment with neutralizing antibodies against cMet (HGF-only receptor). In contrast, we did not observe these effects in rats treated with FK506. However, we observed that the effect of anti-rejection by FK506 was mainly on allostimulated CD4+ T cell (aCD4+ T cell) suppression and regulatory T cell (Treg) promotion, in contrast to the mechanism of HGF. In addition, the protective mechanism of HGF in FK506-mediated nephrotoxicity was addressed. Therefore, HGF as a tolerance inducer, whether used in combination with FK506 or as monotherapy, may have good clinical value. Additional roles of these T-cell subpopulations in other biological systems and studies in these fields will also be meaningful.

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Section: Discussionmentioning

confidence: 54%

“…As such, identification of more reliable ISs to improve graft outcomes in transplant recipients is urgently needed. In recent years, hepatocyte growth factor (HGF) has attracted attention because of its studies in the field of LTx, in particular, its showing a possibility to go across the CD8 + T cell alloimmune barrier ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance

et al. 2023

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“…A) induces CD8 + T cell apoptosis. Bai et al previously show in other biological system that HGF induce both liver tissue-resident and splanic CD8 + T cell apoptosis [21]. Similarly, Reza et al reported [26] increased secretion of HGF in DEN-induced brotic liver disease compared with normal liver (not shown).…”

Section: Discussionmentioning

confidence: 79%

“…However, all of these mechanisms remain largely unknown. Based on studies that discovered of higher HGF secretion in diseased livers compared with normal livers [19,20], we hypothesize that HGF may in uence the survival of CD8 + T cells [21] in both naive and diseased livers. We also hypothesize that excess amounts of HGF perhaps can direct dissociate c-Met binding to Fas on CD8 + T cells, promote Fas accumulation to enhance sensitivity to its ligand FasL, leading to Fas-mediated apoptosis [22].…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte growth factor-mediated apoptosis mechanisms of cytotoxic CD8+ T cells in normal and cirrhotic liver

Bai

Chen

Yan

et al. 2022

Preprint

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Intrahepatic stem/progenitor cells and cytotoxic CD8+ T cells (CD8+ T cells) in the cirrhotic liver undergo apoptosis potentially facilitating progression to cancer. Here, we report that hepatocyte growth factor (HGF) signaling plays an important role in promoting normal and damaged liver CD8+ T cell Fas-mediated apoptotosis through its only receptor c-Met. In addition to binding with HGF, c-Met also binds to Fas as a complex. Using a diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis mouse model, immunofluostaining and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, we identified significantly increased HGF secretion at 10 weeks post-DEN, the liver cirrhotic phase (LCP), compared to it at 3 weeks post-DEN, the liver fibrotic phase (LFP). Correspondingly, difference CD8+ T cell proliferation and apoptosis were noted in the two phases, Interestingly, staining and TUNEL identified that higher smooth muscle actin (α-SMA)+ cell apoptosis, a marker for hepatic stellate cell (HSC) in the LFP compared to their in the LCP, suggesting that beneficial correlation of HGF, CD8+ T cells and HSC in improving fibrotic load during damaged liver repair. In cultures, up to 200 ng/mL amounts of recombinant HGF the naive mouse splenic CD8+ T cells (n-msCD8+ T cells) death, 400 ng/mL rHGF show directly activated death-inducing signaling complex (DISC) to recruit FADD and caspase-8 in both nsCD8+ T cells and healthy human peripheral blood CD8+ T cells (hp-CD8+ T cells), suggesting Fas-mediated apoptosis, may suggest the regulating role of HGF signaling in hepatic homeostasis.

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“…We have currently demonstrated that prolonged oral water feeding with 0.014% DEN produces a sharp line between liver fibrosis (3-5 weeks post-DEN) and cirrhosis cancers (6-10 weeks post-DEN) [18]. Of note, in this model, we have found an interesting phenomenon, showing a positive correlation of resident HSP (NG2 + HSP) survival with hepatic inflammation in the fibrotic stage (3-5 weeks post-DEN) and when an irregular inflammatory response occurred in the later fibrosis or cirrhosis stage (3-5 weeks post-DEN), the HSP cells (NG2 + HSPs) died rapidly (Figure 2A and D), represented as gradually reduced Ki-67 + cells of NG2 + HSPs (Figure 2B) and increased terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL)-expression within the NG2 + HSPs (Figure 2C), suggesting that some unknown signals in the cirrhotic liver niche could trigger the HSP cell (NG2 + HSP) apoptosis [44].…”

Section: (C) the Tunel (Green) Assay Identified Hepatic Resident Ng2 ...mentioning

confidence: 99%

Survival Fate of Hepatic Stem/Progenitor and Immune Cells in a Liver Fibrosis/Cirrhosis Animal Model and Clinical Implications

Yan¹,

Hu²,

Wu³

et al. 2023

Animal Models and Experimental Research in Medicine

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This chapter provides novel information about the survival features of hepatic resident stem/progenitor cells (NG2+ HSPs) during liver fibrosis/cirrhotic development. A well-defined diethylnitrosamine (DEN)-induced liver fibrosis/cirrhotic/cancer mouse model was developed to evaluate the fate of the HSPs and its clinical implications. This model possess three time-zones during the disease development: fibrosis (3–5 weeks post-DEN), cirrhosis (6–10 weeks post-DEN), and cancers (up to 10 weeks post-DEN). During this process, the model represents histological patterns similar to those described in humans and shows better survival of the HSPs in the fibrotic zone, which was correlated with inflammatory signals, as compared to the cirrhotic zone. It has also been discovered that immune CD8+ T cells in the fibrotic zone are beneficial in liver fibrosis resolution, suggesting that the fibrotic time zone is important for mobilizing endogenous HSPs and cell-based therapy. As such, we hypothesize that clinical strategies in fibrotic/cirrhotic liver treatment are necessary either in time at the fibrotic phase or to adopt an approach of regulating HSP viability when the disease develops into the cirrhotic phase.

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Hepatocyte growth factor mediates a novel form of hepatic stem/progenitor cell-induced tolerance in a rat xenogeneic liver rejection model

Cited by 6 publications

References 52 publications

Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance

Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance

Hepatocyte growth factor-mediated apoptosis mechanisms of cytotoxic CD8+ T cells in normal and cirrhotic liver

Survival Fate of Hepatic Stem/Progenitor and Immune Cells in a Liver Fibrosis/Cirrhosis Animal Model and Clinical Implications

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