Mesenchymal stem cell therapy for heart disease

Gnecchi, Massimiliano; Danieli, Patrizia; Cervio, Elisabetta

doi:10.1016/j.vph.2012.04.002

Cited by 135 publications

(82 citation statements)

References 70 publications

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“…Although MSCs are a promising source of cell basic therapy (CBT) for post-MI hearts, MSCs survive poorly when injected into the MI heart, which may limit the functional improvement of the heart through CBT with MSCs [32]. Xing has previously reported that MK promotes self-renewal and proliferation of human embryonic stem cells (hESCs) by inhibiting apoptosis while accelerating the progression toward the S phase and that MK enhances mouse embryonic stem cells (mESCs) self-renewal through the PI3K/Akt signaling pathway [33].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction

Zhao

Zhang

et al. 2014

Stem Cell Res Ther

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IntroductionElevated midkine (MK) expression may contribute to ventricular remodeling and ameliorate cardiac dysfunction after myocardial infarction (MI). Ex vivo modification of signaling mechanisms in mesenchymal stem cells (MSCs) with MK overexpression may improve the efficacy of cell-based therapy. This study sought to assess the safety and efficacy of MSCs with MK overexpression transplantation in a rat model of MI.MethodsA pLenO-DCE vector lentivirus encoding MK was constructed and infected in MSCs. MSC migration activity and cytoprotection was examined in hypoxia-induced H9C2 cells using transwell insert in vitro. Rats were randomized into five groups: sham, MI plus injection of phosphate buffered saline (PBS), MSCs, MSCs-green fluorescent protein (MSCs-GFP) and MSCs-MK, respectively. Survival rates were compared among groups using log-rank test and left ventricular function was measured by echocardiography at baseline, 4, 8 and 12 weeks.ResultsOverexpression of MK partially prevented hypoxia-induced MSC apoptosis and exerted MSC cytoprotection to anoxia induced H9C2 cells. The underlying mechanisms may be associated with the increased mRNA and protein levels of vascular endothelial growth factor (VEGF), transformation growth factor-β (TGF-β), insulin-like growth factor 1 (IGF-1) and stromal cell-derived factor 1 (SDF-1a) in MSCs-MK compared with isolated MSCs and MSCs-GFP. Consistent with the qPCR results, the culture supernatant of MSCs-MK had more SDF-1a (9.23 ng/ml), VEGF (8.34 ng/ml) and TGF-β1 (17.88 ng/ml) expression. In vivo, a greater proportion of cell survival was observed in the MSCs-MK group than in the MSCs-GFP group. Moreover, MSCs-MK administration was related to a significant improvement of cardiac function compared with other control groups at 12 weeks.ConclusionsTherapies employing MSCs with MK overexpression may represent an effective treatment for improving cardiac dysfunction and survival rate after MI.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction

Zhao

Zhang

et al. 2014

Stem Cell Res Ther

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“…Stem cell-based therapy, especially using bone marrow-derived mesenchymal stem cells (MSCs), has been recognized as a promising approach to repair the damaged heart [2]. MSCs have the ability to differentiate into cardiomyocytes or vascular cells, and they have been implicated in cardiac regeneration, formation of microvessels, and paracrine stimulation of surrounding cells [3,4].…”

Section: Introductionmentioning

confidence: 99%

Exogenous miRNA-146a Enhances the Therapeutic Efficacy of Human Mesenchymal Stem Cells by Increasing Vascular Endothelial Growth Factor Secretion in the Ischemia/Reperfusion-Injured Heart

Seo

Lee

et al. 2017

J Vasc Res

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Adult stem cells have been studied as a promising therapeutic modality for the functional restoration of the damaged heart. In the present study, a strategy for enhancing the angiogenic efficacy of human mesenchymal stem cells (hMSCs) using micro-RNA was examined. We investigated whether micro-RNA-146a (miR-146a) influences the secretion of vascular endothelial growth factor (VEGF) and angiogenesis of MSCs. Our data indicated that miR-146a-transfected hMSCs (hMSC^miR-146a) decreased the expression of neurofibromin 2, an inhibitor of p21-activated kinase-1 (PAK1). miR-146a also increased the expression of Ras-related C3 botulinum toxin substrate 1 and PAK1, which are known to induce VEGF expression, and the formation of vascular branches was increased in hMSC^miR-146a compared to hMSCs treated with VEGF. VEGF and p-Akt were increased in hMSC^miR-146a. Furthermore, injection of hMSC^miR-146a after ischemia/reperfusion (I/R) injury led to a reduction of fibrosis area and increased VEGF expression, confirming the regenerative capacity such as reparative angiogenesis in the infarcted area. Cardiac functions in I/R injury were improved following injection of hMSC^miR-146a compared to the I/R group. Taken together, these data suggest that miR-146 is a novel microRNA that regulates VEGF expression, and its use may be an effective strategy for enhancing the therapeutic efficacy of hMSC transplantation into the I/R-injured heart.

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“…In the literature, MSCs are described to home to injured areas and regenerate damaged tissue by either causing cytoprotection, anti-inflammation or by inducing activation of endogenous stem cells ( Gnecchi et al , 2012; Siegel et al , 2012; Williams & Hare, 2011). Recently, it became commonly accepted that possible stem cell effects are derived from the paracrine factors secreted by MSCs ( Di Santo et al , 2009; Jayaraman et al , 2013).…”

Section: Discussionmentioning

confidence: 99%

Secretomes of apoptotic mononuclear cells ameliorate neurological damage in rats with focal ischemia

et al. 2014

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The pursuit of targeting multiple pathways in the ischemic cascade of cerebral stroke is a promising treatment option. We examined the regenerative potential of conditioned medium derived from rat and human apoptotic mononuclear cells (MNC), rMNC apo sec and hMNC apo sec, in experimental stroke.We performed middle cerebral artery occlusion on Wistar rats and administered apoptotic MNC-secretomes intraperitoneally in two experimental settings. Ischemic lesion volumes were determined 48 hours after cerebral ischemia. Neurological evaluations were performed after 6, 24 and 48 hours. Immunoblots were conducted to analyze neuroprotective signal-transduction in human primary glia cells and neurons. Neuronal sprouting assays were performed and neurotrophic factors in both hMNC apo sec and rat plasma were quantified using ELISA.Administration of rat as well as human apoptotic MNC-secretomes significantly reduced ischemic lesion volumes by 36% and 37%, respectively. Neurological examinations revealed improvement after stroke in both treatment groups. Co-incubation of human astrocytes, Schwann cells and neurons with hMNC apo sec resulted in activation of several signaling cascades associated with the regulation of cytoprotective gene products and enhanced neuronal sprouting in vitro. Analysis of neurotrophic factors in hMNC apo sec and rat plasma revealed high levels of brain derived neurotrophic factor (BDNF).Our data indicate that apoptotic MNC-secretomes elicit neuroprotective effects on rats that have undergone ischemic stroke.

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Mesenchymal stem cell therapy for heart disease

Cited by 135 publications

References 70 publications

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction

Exogenous miRNA-146a Enhances the Therapeutic Efficacy of Human Mesenchymal Stem Cells by Increasing Vascular Endothelial Growth Factor Secretion in the Ischemia/Reperfusion-Injured Heart

Secretomes of apoptotic mononuclear cells ameliorate neurological damage in rats with focal ischemia

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