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

Departments of Cardiothoracic Surgery, Stanford University, CA 94305-5407, USA.
Circulation (Impact Factor: 14.43). 09/2009; 120(11 Suppl):S247-54. DOI: 10.1161/CIRCULATIONAHA.108.843680
Source: PubMed


Mesenchymal stem cell (MSC)-based regenerative strategies were investigated to treat acute myocardial infarction and improve left ventricular function.
Murine AMI was induced by coronary ligation with subsequent injection of MSCs, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), or MSCs +HGF/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.
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.

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    • "Actually, VEGF, as a key angiogenic and growth factor from MSC, is important for maintaining or improving normal cardiac function in MSC-mediated cardiac repair through promoting angiogenesis and inhibiting cardiocyte apoptosis [14] [15]. More importantly, the genetic modification and preconditioning by VEGF protein may better enhance MSC survival [16] [17]. Recent studies have shown that c-Kit+ CSCs express VEGF-R (Flt-1 and Flk/KDR) [18], and VEGF contributes to the myogenic cluster formation of MSCs and CSCs [19]. "
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    ABSTRACT: The objective of this study was to determine whether vascular endothelial growth factor (VEGF)-A subtypes improve cardiac stem cell (CSC) engraftment and promote CSC-mediated myocardial repair in the infarcted heart. CSCs were treated with VEGF receptor (VEGFR) inhibitors, VCAM-1 antibody (VCAM-1-Ab), or PKC-α inhibitor followed by the treatment with VEGF-A. CSC adhesion assays were performed in vitro. In vivo, the PKH26-labeled and VCAM-1-Ab or PKC-α inhibitor pre-treated CSCs were treated with VEGF-A followed by implantation into infarcted rat hearts. The hearts were then collected for measuring CSC engraftment and evaluating cardiac fibrosis and function 3 or 28days after the CSC transplantation. All three VEGF-A subtypes promoted CSC adhesion to extracellular matrix and endothelial cells. VEGF-A-mediated CSC adhesion required VEGFR and PKCα signaling. Importantly, VEGF-A induced VCAM-1, but not ICAM-1 expression in CSCs through PKCα signaling. In vivo, VEGF-A promoted the engraftment of CSCs in infarcted hearts, which was attenuated by PKCα inhibitor or VCAM-1-Ab. Moreover, VEGF-A-mediated CSC engraftment resulted in a reduction in infarct size and fibrosis. Functional studies showed that the transplantation of the VEGF-A-treated CSCs stimulated extensive angiomyogenesis in infarcted hearts as indicated by the expression of cardiac troponin T and von Willebrand factor, leading to an improved performance of left ventricle. Blockade of PKCα signaling or VCAM-1 significantly diminished the beneficial effects of CSCs treated with VEGF-A. VEGF-A promotes myocardial repair through, at least in part, enhancing the engraftment of CSCs mediated by PKCα/VCAM-1 pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jan 2015 · International Journal of Cardiology
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    • "While clinical meta-analyses have suggested small to modest effects (Delewi et al., 2013; Jeevanantham et al., 2012) and further phase III human studies are ongoing (Sheridan, 2013), meaningful improvements in clinical outcomes and even surrogate measures remain to be convincingly demonstrated. Although a possible exception may be bone-marrow derived mesenchymal stem cell therapy (Heldman et al., 2014; Hare et al., 2012), potential beneficial effects appear predominantly due to paracrine signaling from the administered cell population, which often fails to engraft and survive beyond 1–2 weeks (Fang et al., 2011; Deuse et al., 2009). While paracrine signaling might help hypoxic or metabolically challenged cardiomyocytes survive an acute insult, it is difficult to conceptually envision how short-term paracrine effects could help improve vascularization in the long-term, especially when the clinical experience with hibernating myocardium and revascularization suggests that large, epicardial-like vessels are required for adequate myocardial perfusion. "
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    ABSTRACT: The history of revascularization for cardiac ischemia dates back to the early 1960's when the first coronary artery bypass graft procedures were performed in humans. With this 50year history of providing a new vasculature to ischemic and hibernating myocardium, a profound depth of experience has been amassed in clinical cardiovascular medicine as to what does, and does not work in the context of cardiac revascularization, alleviating ischemia and adequacy of myocardial perfusion. These issues are of central relevance to contemporary cell-based cardiac regenerative approaches. While the cardiovascular cell therapy field is surging forward on many exciting fronts, several well accepted clinical axioms related to the cardiac arterial supply appear to be almost overlooked by some of our current basic conceptual and experimental cell therapy paradigms. We present here information drawn from five decades of the clinical revascularization experience, review relevant new data on vascular formation via cell therapy, and put forward the case that for optimal cell-based cardiac regeneration due attention must be paid to providing an adequate vascular supply.
    Full-text · Article · Apr 2014 · Stem Cell Research
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    • "WJ-MSC produced almost undetectable amounts of VEGF; on the other hand, AT- and BM-MSC were the highest VEGF producers. Research articles like those published by Deuse’s and Augustin’s groups showed that MSC genetically modified to overexpress VEGF are more appropriate than MSC alone for treating acute myocardial infarction, as VEGF extended MSC survival and protected them against apoptosis and improved heart function recovery [36,37]. This information suggests that BM- and AT-MSC would be better candidates for infarction therapy than WJ-MSC. "
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    ABSTRACT: Different mesenchymal stromal cells (MSC) have been successfully isolated and expanded in vitro and nowadays they are tested in clinical trials for a wide variety of diseases. Whether all MSC express the same cell surface markers or have a similar secretion profile is still controversial, making it difficult to decide which stromal cell may be better for a particular application. We isolated human mesenchymal stromal cells from bone marrow (BM), adipose tissue (AT) and Wharton's jelly (WJ) and cultured them in fetal bovine serum supplemented media. We evaluated proliferation, in vitro differentiation (osteogenic, adipogenic and chondrogenic potential), expression of cell surface markers and protein secretion using Luminex and ELISA assays. Cell proliferation was higher for WJ-MSC, followed by AT-MSC. Differences in surface expression markers were observed only for CD54 and CD146. WJ-MSC secreted higher concentrations of chemokines, pro-inflammatory proteins and growth factors. AT-MSC showed a better pro-angiogenic profile and secreted higher amounts of extracellular matrix components and metalloproteinases. Mesenchymal stromal cells purified from different tissues have different angiogenic, inflammatory and matrix remodeling potential properties. These abilities should be further characterized in order to choose the best protocols for their therapeutic use.
    Full-text · Article · Apr 2014 · Stem Cell Research & Therapy
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