A promising strategy for the treatment of ischemic heart disease: Mesenchymal stem cell-mediated vascular endothelial growth factor gene transfer in rats

Gao, Feng; He, Tao; Wang, Hongbing; Yu, Shiqiang; Liu, Weiyong; Zhang, Cai

doi:10.1016/s0828-282x(07)70845-0

Cited by 80 publications

(41 citation statements)

References 27 publications

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“…Earlier studies using HGF or VEGF overexpressing MSCs after AMI 20,27 may have overestimated the transdifferentiation potential of MSCs with incorporation into the ischemic myocardium, which is not supported by our current knowledge. 28 It is unknown for how long the elevated cytokine concentrations are needed in the healing heart and for how long they remain beneficial.…”

Section: S252 Circulation September 15 2009contrasting

confidence: 72%

Hepatocyte Growth Factor or Vascular Endothelial Growth Factor Gene Transfer Maximizes Mesenchymal Stem Cell–Based Myocardial Salvage After Acute Myocardial Infarction

et al. 2009

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Background-Mesenchymal stem cell (MSC)-based regenerative strategies were investigated to treat acute myocardial infarction and improve left ventricular function. Methods and Results-Murine AMI was induced by coronary ligation with subsequent injection of MSCs, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), or MSCs ϩHGF/VEGF into the border zone. Left ventricular ejection fraction was calculated using micro-computed tomography imaging after 6 months. HGF and VEGF protein injection (with or without concomitant MSC injection) significantly and similarly improved the left ventricular ejection fraction and reduced scar size compared with the MSC group, suggesting that myocardial recovery was due to the cytokines rather than myocardial regeneration. To provide sustained paracrine effects, HGF or VEGF overexpressing MSCs were generated (MSC-HGF, MSC-VEGF). MSC-HGF and MSC-VEGF showed significantly increased in vitro proliferation and increased in vivo proliferation within the border zone. Cytokine production correlated with MSC survival. MSC-HGF-and MSC-VEGF-treated animals showed smaller scar sizes, increased peri-infarct vessel densities, and better preserved left ventricular function when compared with MSCs transfected with empty vector. Murine cardiomyocytes were exposed to hypoxic in vitro conditions. The LDH release was reduced, fewer cardiomyocytes were apoptotic, and Akt activity was increased if cardiomyocytes were maintained in conditioned medium obtained from MSC-HGF or MSC-VEGF cultures. Conclusions-This study showed that (1) elevating the tissue levels of HGF and VEGF after acute myocardial infarction seems to be a promising reparative therapeutic approach, (2) HGF and VEGF are cardioprotective by increasing the tolerance of cardiomyocytes to ischemia, reducing cardiomyocyte apoptosis and increasing prosurvival Akt activation, and (3) MSC-HGF and MSC-VEGF are a valuable source for increased cytokine production and maximize the beneficial effect of MSC-based repair strategies. However, the optimal MSC source (bone marrow versus adipose tissue), the ideal application method (intracoronary versus intramyocardial), and the underlying mechanisms are unclear. Although initially aimed at regeneration, MSC therapy may limit maladaptive remodeling and improve heart function mainly through paracrine mechanisms in the absence of regeneration. Due to the stressful procedure of cell harvest causing morphological changes with loss of spindle-shaped fibroblast-like shape and intercellular connections and shear stress during needle aspiration and cell injection, combined with a harsh milieu in the ischemic heart of the host, substantial cell losses are common early after cell transplantation. 3 Despite these significant losses, beneficial effects on cardiac remodeling have been consistently observed, andFrom the Departments of Cardiothoracic Surgery (T.D., W.S., R.C.R., S.S.) and Cardiovascular Medicine (C.P., J.C.W.), and Pediatrics (T.D.), Stanford University, Stanford, Calif; Libin Cardiova...

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Section: S252 Circulation September 15 2009contrasting

confidence: 72%

Hepatocyte Growth Factor or Vascular Endothelial Growth Factor Gene Transfer Maximizes Mesenchymal Stem Cell–Based Myocardial Salvage After Acute Myocardial Infarction

et al. 2009

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“…The therapeutic benefits of Akt-MSCs, at least in the acute phase of MI, seem to be due to diffusible factors released by the cells such as VEGF, fibroblast growth factor (FGF)-2, HGF, IGF-I, and thymosin B4, which act in a paracrine fashion to limit infarct size and improve ventricular function [53,54]. Also, compared with unmodified cells, MSCs transfected with VEGF exhibited significantly higher levels of myocardial angiogenesis and cardiomyocyte regeneration, and prevented progressive scar formation and heart dysfunction in a rodent model of myocardial ischaemia [55]. Consistently, our group has reported similar results in human cord bloodderived haematopoietic cells overexpressing VEGF and PDGF [42].…”

Section: Stem Cell Modifications and Cardiac Fibrosismentioning

confidence: 99%

Stem cell transplantation as a therapy for cardiac fibrosis

Elnakish

Kuppusamy

Khan

2012

The Journal of Pathology

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Cardiac fibrosis is a fundamental constituent of most cardiac pathologies and represents the upshot of nearly all types of cardiac injury. Generally, fibrosis is a scarring process, characterized by accumulation of fibroblasts and deposition of increasing amounts of extracellular matrix (ECM) proteins in the myocardium. Therapeutic approaches that control fibroblast activity and evade maladaptive processes could represent a potential strategy to attenuate progression towards heart failure. Currently, cell therapy is actively perceived as an alternative to traditional pharmacological management of myocardial infarction (MI). The majority of the studies applying stem cell therapy following MI have demonstrated a decline in fibrosis. However, it was not clearly recognized whether the decline in cardiac fibrosis was due to replacement of dead cardiomyocytes or because of the direct effects of paracrine factors released from the transplanted stem cells on the ECM. Therefore, the main focus of this review is to discuss the impact of different types of stem cells on cardiac fibrosis and associated cardiac remodelling in a variety of experimental models of heart failure, particularly MI.

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“…For instance, it has been observed that the transplantation of tumor necrosis factor receptor (TNFR) gene-modified MSCs induced an anti-inflammatory effect and inhibited the apoptotic death of resident cardiomyocytes, and thereby improved the left ventricular function in rat with acute myocardial infraction [132]. Similarly, the transplantation of adenovirus carrying human vascular endothelial growth factor 165 (Ad-hVEGF165) gene-transfected MSCs into rats with ischemic heart disease significantly promoted the host-derived angiogenesis and produced effective myogenesis as compared to MSCs transplant [133]. The transplantation of angiogenin-overexpressing human MSCs obtained after infection with adenovirus containing angiogenin gene (AdAng) also improved the heart perfusion and function in a porcine model of chronic ischemia as compared to MSC (AdNull) [134].…”

Section: Cardiac Stem/progenitor Cells and Their Therapeutic Applicatmentioning

confidence: 99%

Recent Progress on Tissue-Resident Adult Stem Cell Biology and Their Therapeutic Implications

2008

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Recent progress in the field of the stem cell research has given new hopes to treat and even cure diverse degenerative disorders and incurable diseases in human. Particularly, the identification of a rare population of adult stem cells in the most tissues/organs in human has emerged as an attractive source of multipotent stem/progenitor cells for cell replacement-based therapies and tissue engineering in regenerative medicine. The tissue-resident adult stem/progenitor cells offer the possibility to stimulate their in vivo differentiation or to use their ex vivo expanded progenies for cell replacement-based therapies with multiple applications in human. Among the human diseases that could be treated by the stem cell-based therapies, there are hematopoietic and immune disorders, multiple degenerative disorders, such as Parkinson's and Alzeimeher's diseases, type 1 or 2 diabetes mellitus as well as eye, liver, lung, skin and cardiovascular disorders and aggressive and metastatic cancers. In addition, the genetically-modified adult stem/progenitor cells could also be used as delivery system for expressing the therapeutic molecules in specific damaged areas of different tissues. Recent advances in cancer stem/progenitor cell research also offer the possibility to targeting these undifferentiated and malignant cells that provide critical functions in cancer initiation and progression and disease relapse for treating the patients diagnosed with the advanced and metastatic cancers which remain incurable in the clinics with the current therapies.

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A promising strategy for the treatment of ischemic heart disease: Mesenchymal stem cell-mediated vascular endothelial growth factor gene transfer in rats

Cited by 80 publications

References 27 publications

Hepatocyte Growth Factor or Vascular Endothelial Growth Factor Gene Transfer Maximizes Mesenchymal Stem Cell–Based Myocardial Salvage After Acute Myocardial Infarction

Hepatocyte Growth Factor or Vascular Endothelial Growth Factor Gene Transfer Maximizes Mesenchymal Stem Cell–Based Myocardial Salvage After Acute Myocardial Infarction

Stem cell transplantation as a therapy for cardiac fibrosis

Recent Progress on Tissue-Resident Adult Stem Cell Biology and Their Therapeutic Implications

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