HGF/c-Met Signaling Mediated Mesenchymal Stem Cell-induced Liver Recovery in Intestinal Ischemia Reperfusion Model

Liu, Jianpei; Pan, Guozheng; Liang, Tangzhao; Huang, Pinjie

doi:10.7150/ijms.8228

Cited by 38 publications

(35 citation statements)

References 43 publications

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“…Moreover, c-Met has been deemed to be an important signaling molecule in the clinical application of MSCs in ischemia [19]. Our present results showed that hypoxia induces an increase in c-Met expression in MSCs cultured in hypoxic conditions in vitro .…”

Section: Discussionsupporting

confidence: 71%

“…The same phenomenon has been observed in vascular ulcers; the activity of HGF and c-Met in arterial MSCs supplements cell migration, angiogenesis, and vasculogenesis [18]. Moreover, pretreatment of MSCs with HGF enhances their ability to respond to ischemia by promoting cell migration and cytokine secretion, which augment regeneration and wound healing [19]. Although the ability of HGF/c-Met to facilitate mobility and support the repair functions of MSCs has been reported, the interaction between c-Met and the prion proteins that are upregulated during ischemic hypoxia has not yet been well studied.…”

Section: Introductionmentioning

confidence: 73%

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C-Met-Activated Mesenchymal Stem Cells Rescue Ischemic Damage via Interaction with Cellular Prion Protein

Han

Yun

Lee

et al. 2018

Cell Physiol Biochem

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Background/Aims: Stem cell transplantation has emerged as a promising therapeutic strategy, but the exact mechanisms by which stem cells exposed to hypoxic conditions increase the survival rate and rescue ischemic injury at the graft site are not well known. In this study, we aimed to determine if c-Met-activated mesenchymal stem cells (MSCs) pre-exposed to hypoxia promote therapeutic efficacy when transplanted to ischemic models, and whether c-Met interacts with cellular prion protein (PrP^C) present in the ischemic tissue. Methods: Western blot analysis was performed to determine the expression levels of PrP^C, C-caspase-3, and C-PARP-1, as well as the phosphorylation of Akt, p38, JNK, and BAX. A co-immunoprecipitation assay was performed to show that PrP^C binds with c-Met in vitro. An adhesion assay was performed to explore the alterations in MSCs attached to myoblasts (in vitro), and an invasion assay was performed to determine the effect on MSC invasion capacity upon interaction with myoblast-induced c-Met and PrP^C. CD31-positive capillaries and αSMA-positive arterioles in in vivo hindlimb ischemic tissue were quantified by immunofluorescence staining. The level of apoptosis in the tissue of each group was assessed by quantifying the number of C-caspase-3-positive cells. Finally, laser Doppler technology was utilized to detect the enhanced angiogenic effects in vivo. Results: We showed that hypoxic conditions increased PrP^C levels in vivo (hindlimb ischemic tissue) and in vitro (myoblasts) and increased c-Met levels in MSCs. To identify the relationship between c-Met from MSCs and PrP^C from myoblasts, we used a co-culturing system with myoblasts and MSCs pre-exposed to hypoxia. Hypoxia increased the phosphorylation of mitogen-activated protein kinases. Transplantation of hypoxia-pre-exposed MSCs to the ischemic site increased anti-apoptosis and enhanced the survival and proliferation of transplanted MSCs in a murine hindlimb model, resulting in improved functional recovery of the ischemic tissue. All the aforementioned effects were inhibited by the pretreatment of MSCs with the c-Met-neutralizing antibody Conclusion: c-Met-activated MSCs pre-exposed to hypoxia interact with PrP^C at the site of ischemic injury to increase the efficiency of MSC transplantation. Hence, our study demonstrated that c-Met is a potential target for MSC-based therapies.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 73%

C-Met-Activated Mesenchymal Stem Cells Rescue Ischemic Damage via Interaction with Cellular Prion Protein

Han

Yun

Lee

et al. 2018

Cell Physiol Biochem

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“…(46) demonstrated a concomitant rise in hepatocyte growth factor (HGF) and Met‐P expression after MSC treatment, which they hypothesized may modulate either MSC action or homing to areas of injury. In fact, the HGF/c‐Met signaling pathway has been shown to be critical to MSC homing to the liver in an acute ischemic liver injury model in rats, as subsequently confirmed by transwell in vitro studies (112). Furthermore, Ishikawa et al .…”

Section: Can Mscs Deliver a Direct Antifibrotic Effect?mentioning

confidence: 84%

Mesenchymal stromal cells and liver fibrosis: a complicated relationship

et al. 2016

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Mesenchymal stromal cell (MSC) therapy demands the attention of clinicians and scientists because of its potential in clinical fields that are bereft of medical options, but also because of the controversies that underlie its mode of action. MSCs are potent immune modulators, yet their biologic activity may not be innate, requiring licensing by their microenvironment. This property has prompted researchers to explore unique ways in which MSCs may be able to exert distinct biologic effects in different pathologic settings. More than 400 clinical trials have investigated the therapeutic capacity of MSCs in different pathologies, including liver disease. Along with their anti-inflammatory action, there are data to suggest that MSCs may exert direct antifibrotic effects, although enthusiasm for their use in patients has been tempered by concerns of a possible profibrotic role of endogenous MSCs in response to injury. There is a significant need for antifibrotic therapy to combat the increasing burden of patients with cirrhosis, and a concerted effort is required to determine the mechanisms by which MSCs modulate the liver's response to injury, both endogenously and after adoptive transfer. This review critically appraises the preclinical published data with regard to the capacity of MSCs to influence fibrotic response to liver injury and will explore the potential mechanisms that underpin the reported beneficial effects of MSC therapy in the context of liver injury and fibrosis.-Haldar, D., Henderson, N. C., Hirschfield, G., Newsome, P. N. Mesenchymal stromal cells and liver fibrosis: a complicated relationship.

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“…Moreover, the pathophysiology of remote liver injury after intestinal I/R remains only partially understood; putative mechanisms include sustained pro‐inflammatory cytokine challenge and cytokines that are released or activated after enterocyte damage or death . If liver repair and regenerative mechanisms are not activated promptly, especially in patients with chronic liver disease or after liver transplantation, acute liver functional impairment, or poor early graft function will occur . Despite extensive studies, effective multiple organ protective interventions with clinically proven efficacy remain to be developed.…”

Section: Introductionmentioning

confidence: 99%

HMGB1‐associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats

Wen

Ling

et al. 2020

FASEB j.

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Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor‐interacting protein kinase 1/3 (RIP1/3) and phosphorylated‐MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage‐depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What’s more, HMGB1 neutralization further protects against intestinal I/R‐associated liver damage in microbiota‐depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec‐1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R‐induced acute remote organ dysfunction.

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HGF/c-Met Signaling Mediated Mesenchymal Stem Cell-induced Liver Recovery in Intestinal Ischemia Reperfusion Model

Cited by 38 publications

References 43 publications

C-Met-Activated Mesenchymal Stem Cells Rescue Ischemic Damage via Interaction with Cellular Prion Protein

C-Met-Activated Mesenchymal Stem Cells Rescue Ischemic Damage via Interaction with Cellular Prion Protein

Mesenchymal stromal cells and liver fibrosis: a complicated relationship

HMGB1‐associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats

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