Hepatocyte Growth Factor Modification Enhances the Anti-Arrhythmic Properties of Human Bone Marrow-Derived Mesenchymal Stem Cells

Zhang, Jian; Wang, Lin-Lin; Du, Wei; Yu, Yichao; Ju, Weizhu; Man, Yi-Long; Li, Xiaorong; Chen, Yan; Wang, Zi-Dun; Gu, Wei; Zhang, Fengxiang; Wang, Hua; Wu, Chu-Tse; Cao, Kejiang

doi:10.1371/journal.pone.0111246

Cited by 13 publications

(13 citation statements)

References 37 publications

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“…Likewise, CXCR4, SDF‐1 and HGF hyperexpression were found to improve homing of MSCs in the peri‐infarct area, attenuate LV remodelling and improve contractility. In addition, intramyocardial injection of HGF‐MSC in infarcted pigs resulted in decreased density of sympathetic nerve endings, better electrical stability of the heart and decreased arrhythmias . Integrin‐linked kinase (ILK) directly interacts with integrin molecules, thereby playing an indispensable role in integrin‐mediated cell adhesion and signalling.…”

Section: Genetic Modification Of Mscsmentioning

confidence: 99%

Can the outcomes of mesenchymal stem cell‐based therapy for myocardial infarction be improved? Providing weapons and armour to cells

et al. 2016

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Use of mesenchymal stem cell (MSC) transplantation after myocardial infarction (MI) has been found to have infarct-limiting effects in numerous experimental and clinical studies. However, recent meta-analyses of randomized clinical trials on MSC-based MI therapy have highlighted the need for improving its efficacy. There are two principal approaches for increasing therapeutic effect of MSCs: (i) preventing massive MSC death in ischaemic tissue and (ii) increasing production of cardioreparative growth factors and cytokines with transplanted MSCs. In this review, we aim to integrate our current understanding of genetic approaches that are used for modification of MSCs to enable their improved survival, engraftment, integration, proliferation and differentiation in the ischaemic heart. Genetic modification of MSCs resulting in increased secretion of paracrine factors has also been discussed. In addition, data on MSC preconditioning with physical, chemical and pharmacological factors prior to transplantation are summarized. MSC seeding on three-dimensional polymeric scaffolds facilitates formation of both intercellular connections and contacts between cells and the extracellular matrix, thereby enhancing cell viability and function. Use of genetic and non-genetic approaches to modify MSC function holds great promise for regenerative therapy of myocardial ischaemic injury.

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Section: Genetic Modification Of Mscsmentioning

confidence: 99%

Can the outcomes of mesenchymal stem cell‐based therapy for myocardial infarction be improved? Providing weapons and armour to cells

et al. 2016

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“…Many studies have been performed to improve the effectiveness of cardiovascular therapy using a variety of populations, including CSC and cardiomyocyte progenitors genetically engineered using the αMHC promoter [ 26 ]. Although the effects of administering different cell types or growth factors, separately and independently, have been analyzed [ 27 , 28 ], few studies have examined their combined effect [ 29 ]. Here, we explored the combination of cell and gene therapy strategies using MSC genetically modified to overexpress IGF-1 or HGF growth factors as a single treatment in a porcine AMI model.…”

Section: Introductionmentioning

confidence: 99%

Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model

et al. 2016

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BackgroundInsulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are among the most promising growth factors for promoting cardiorepair. Here, we evaluated the combination of cell- and gene-based therapy using mesenchymal stem cells (MSC) genetically modified to overexpress IGF-1 or HGF to treat acute myocardial infarction (AMI) in a porcine model.MethodsPig MSC from adipose tissue (paMSC) were genetically modified for evaluation of different therapeutic strategies to improve AMI treatment. Three groups of infarcted Large White pigs were compared (I, control, non-transplanted; II, transplanted with paMSC-GFP (green fluorescent protein); III, transplanted with paMSC-IGF-1/HGF). Cardiac function was evaluated non-invasively using magnetic resonance imaging (MRI) for 1 month. After euthanasia and sampling of the animal, infarcted areas were studied by histology and immunohistochemistry.ResultsIntramyocardial transplant in a porcine infarct model demonstrated the safety of paMSC in short-term treatments. Treatment with paMSC-IGF-1/HGF (1:1) compared with the other groups showed a clear reduction in inflammation in some sections analyzed and promoted angiogenic processes in ischemic tissue. Although cardiac function parameters were not significantly improved, cell retention and IGF-1 overexpression was confirmed within the myocardium.ConclusionsThe simultaneous administration of IGF-1- and HGF-overexpressing paMSC appears not to promote a synergistic effect or effective repair. The combined enhancement of neovascularization and fibrosis in paMSC-IGF-1/HGF-treated animals nonetheless suggests that sustained exposure to high IGF-1 + HGF levels promotes beneficial as well as deleterious effects that do not improve overall cardiac regeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0350-z) contains supplementary material, which is available to authorized users.

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“…These stimuli activate the Met pathway, exert strong antiapoptotic effects on cardiomyocytes (18)(19)(20), and induce endothelial cell migration by activating Rac1 (21). A study on a pig model of MI showed that treatment with mesenchymal stem cells with modifications in the HGF gene (HGF-MSCs) increases vascular density and Cx43 expression and induces a lower apoptosis rate and a reduced occurrence of ventricular arrhythmias compared with those induced by treatment with unmodified MSCs (22). Intriguingly, the presence of HGF alone recapitulates most of the effects shown in our research.…”

Section: Discussionmentioning

confidence: 99%

Combination of HGF and IGF-1 promotes connexin 43 expression and improves ventricular arrhythmia after myocardial infarction through activating the MAPK/ERK and MAPK/p38 signaling pathways in a rat model

Yao¹,

Ke²,

Zhou³

et al. 2019

Cardiovasc. Diagn. Ther.

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Background: In this study, we hypothesized that the combination of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) alters the expression of connexin 43 (Cx43) and results in a reduced frequency of induced ventricular arrhythmia in rats after myocardial infarction (MI) and explored the preliminary mechanisms involved. Methods: Cardiomyocytes were cultured in vitro in medium with PBS, HGF, IGF-1, GFs (HGF + IGF-1), HGF + p38 inhibitor, HGF + ERK inhibitor, IGF-1 + p38 inhibitor or IGF-1 + ERK inhibitor. The expression of Cx43 was tested by real-time PCR and Western blotting after 48 hours. MI was induced in 48 male Sprague-Dawley rats. The rats were randomly divided into four groups and received an injection of PBS, HGF, IGF-1 or GFs into the infarct border zone two weeks after MI. Six weeks after injection, the expression levels of Cx43 and programmed stimulation-induced ventricular arrhythmias were examined. Results: In vitro, the expression of Cx43 mRNA and the Cx43 protein in cardiomyocytes was higher in the HGF, IGF-1, and GFs groups than in the PBS group. GFs had a combinatorial effect on the Cx43 mRNA level but not on the Cx43 protein level. There was a significant reduction in Cx43 mRNA and Cx43 protein levels in the IGF-1 + p38 inhibitor group and IGF-1 + ERK inhibitor group compared to the IGF-1 group. In vivo, programmed stimulation significantly decreased the frequency of ventricular arrhythmia in the GFs, HGF and IGF-1 groups, and this effect was accompanied by increased immunohistochemical staining for Cx43, myocardial Cx43 protein levels and Cx43 mRNA levels in the infarct border zone of the left ventricle compared with those in the PBS group. The combinatorial effect of GFs on Cx43 expression was only observed at the mRNA level. Conclusions: Both HGF and IGF-1 enhanced the expression of Cx43 and improved induced ventricular arrhythmia in rats with MI. Both synergistic and antagonistic effects of HGF and IGF-1 were not observed. In addition, IGF-1 may function through the MAPK/p38 and ERK1/2 signaling pathways to regulate Cx43 expression.

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Hepatocyte Growth Factor Modification Enhances the Anti-Arrhythmic Properties of Human Bone Marrow-Derived Mesenchymal Stem Cells

Cited by 13 publications

References 37 publications

Can the outcomes of mesenchymal stem cell‐based therapy for myocardial infarction be improved? Providing weapons and armour to cells

Can the outcomes of mesenchymal stem cell‐based therapy for myocardial infarction be improved? Providing weapons and armour to cells

Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model

Combination of HGF and IGF-1 promotes connexin 43 expression and improves ventricular arrhythmia after myocardial infarction through activating the MAPK/ERK and MAPK/p38 signaling pathways in a rat model

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