Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure

Wang, Kun; Li, Yuwen; Zhu, Tiantian; Zhang, Yongting; Li, Wenting; Lin, Wenyu; Li, Jun; Zhu, Chuanlong

doi:10.1186/s13287-017-0614-2

Cited by 39 publications

(25 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…c-Met has been recently suggested to play a significant role in MSC proliferation and its clinical applications [16, 17]. Moreover, c-Met has been deemed to be an important signaling molecule in the clinical application of MSCs in ischemia [19].…”

Section: Discussionmentioning

confidence: 99%

“…Although c-Met is typically expressed in epithelial cells, studies have suggested that its functional form is also expressed in MSCs, indicating that it may play a role in mobilizing these stem cells and helping them in the wound healing process [16]. Previous studies have demonstrated that c-Met enhances the ability of MSCs to migrate to the sites of injury after acute liver failure [17]. 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].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Han

Yun

Lee

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Han

Yun

Lee

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…MSCs significantly improved the survival and liver function of ALF rats, as these cells showed enhanced homing to the injured liver. 75 Forkhead box P3 (Foxp-3)-overexpressing MSCs significantly inhibited the differentiation of CD4+ T cells into splenocytes in a contactdependent manner, while Foxp3-overexpressing MSCs transformed CD4+ T cells into Tregs and generated donor-specific liver allograft tolerance. 76 Overexpression of target genes in MSCs will induce insertional mutagenesis and epigenetic alterations; thus, we should examine these obstacles in future studies.…”

Section: Pre-treatments With An Altered Microenvironment For Msc-bamentioning

confidence: 99%

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

Wang

2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Liver diseases caused by viral infection, alcohol abuse and metabolic disorders can progress to end‐stage liver failure, liver cirrhosis and liver cancer, which are a growing cause of death worldwide. Although liver transplantation and hepatocyte transplantation are useful strategies to promote liver regeneration, they are limited by scarce sources of organs and hepatocytes. Mesenchymal stem cells (MSCs) restore liver injury after hepatogenic differentiation and exert immunomodulatory, anti‐inflammatory, antifibrotic, antioxidative stress and antiapoptotic effects on liver cells in vivo. After isolation and culture in vitro, MSCs are faced with nutrient and oxygen deprivation, and external growth factors maintain MSC capacities for further applications. In addition, MSCs are placed in a harsh microenvironment, and anoikis and inflammation after transplantation in vivo significantly decrease their regenerative capacity. Pre‐treatment with chemical agents, hypoxia, an inflammatory microenvironment and gene modification can protect MSCs against injury, and pre‐treated MSCs show improved hepatogenic differentiation, homing capacity, survival and paracrine effects in vitro and in vivo in regard to attenuating liver injury. In this review, we mainly focus on pre‐treatments and the underlying mechanisms for improving the therapeutic effects of MSCs in various liver diseases. Thus, we provide evidence for the development of MSC‐based cell therapy to prevent acute or chronic liver injury. Mesenchymal stem cells have potential as a therapeutic to prolong the survival of patients with end‐stage liver diseases in the near future.

show abstract

“…In the current MSC transplantation, only a few MSCs can colonize the liver, and we can improve the hepatic colonizability by modifying MSCs. c-Met-MSCs significantly enhanced the homing ability to the injured liver and increased the survival rate and liver function in rats with liver failure [ 73 ]. A similar study demonstrated that MSCs expressing C-X-C chemokine receptor type 4 (CXCR4) had greater hepatic colonizability and contributed to restore the damaged liver [ 74 , 75 ].…”

Section: Introductionmentioning

confidence: 99%

“…Tang et al reported that UC-MSCs overexpressing HGF can reduce liver damage and prolong the survival rate of APAP-induced ALF mice through anti-apoptosis and anti-oxidation [ 82 ]. Wang et al found that c-Met expression in hepatocytes is closely associated with HGF-mediated liver regeneration [ 73 ]. Hepatocytes could specifically express the c-Met gene through gene transfer in vivo , thus enhancing hepatocyte proliferation, decreasing apoptosis, and significantly improving overall survival rates [ 83 ].…”

Section: Introductionmentioning

confidence: 99%

Progress in mesenchymal stem cell–based therapy for acute liver failure

Wang

Chen

et al. 2018

Stem Cell Res Ther

View full text Add to dashboard Cite

Acute liver failure is a life-threatening clinical syndrome characterized by rapid development of hepatocellular necrosis leading to high mortality and resource costs. Numerous treatment strategies for acute liver failure simply prevent complications and decelerate disease progression. The only curative treatment for acute liver failure is liver transplantation, but there are many restrictions on the application of liver transplantation. In recent years, a growing number of studies have shown that stem cells can effectively treat acute liver failure. Several types of stem cells have been used to study liver diseases; mesenchymal stem cells are most commonly used because they are easy to obtain and present no ethical problems. The aims of this article are to review the current knowledge regarding therapeutic mechanisms of mesenchymal stem cells in acute liver failure, to discuss recent advancements in preclinical and clinical studies in the treatment of mesenchymal stem cells, and to summarize the methodological improvement of mesenchymal stem cell transplantation in treating liver failure.

show abstract

Overexpression of c-Met in bone marrow mesenchymal stem cells improves their effectiveness in homing and repair of acute liver failure

Cited by 39 publications

References 35 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

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

Progress in mesenchymal stem cell–based therapy for acute liver failure

Contact Info

Product

Resources

About