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

Abstract

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.

Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model

“…Since the porcine endogenous CSCs have an intact signalling IGF-1/HGF receptor system, the type of growth factor used in our investigation is considered as a good option for MI therapy 14 . Although the effects of administering different growth factors have been analysed in previous experiments 20 , to the best of our knowledge there are no studies that have examined the effect when delivered after its microencapsulation as a way to increase release time in a single intervention.…”

Overexpression of anti-fibrotic factors ameliorates anti-fibrotic properties of Wharton's jelly derived mesenchymal stem cells under oxidative damage

“…It has been shown that HGF prevented the progression of fibrogenesis in multiple organs such as lung, liver and heart (36,38,39). IGF1 exerts the beneficial effect on cardiac repair by enhancing angiogenesis and improving myocardial function (40). Previous studies demonstrated that SHH inhibited cardiac fibrosis, at least in part, by stimulating the production of paracrine factors that exert anti-fibrotic action (41).…”

Unmodified, autologous adipose-derived regenerative cells improve cardiac function, structure and revascularization in a porcine model of chronic myocardial infarction

“…Furthermore, porcine models allow the opportunity to evaluate the therapeutic outcome with MRI, which is considered to provide the most accurate, comprehensive and reproducible measurements of cardiac chamber dimensions, volumes, function and infarct size compared with other techniques 8 . Unfortunately, in those studies on porcine and sheep models in which treatment success of cell-based therapies for (experimentally induced) MI was assessed using MRI, temporary occlusion of the left anterior descending (LAD) artery was (except of one study that showed no success 26 ) restricted to 60 min 27,28 or 90 min 29,30 . As a result, in most of these studies 27,28,30 the left ventricular ejection fraction (LVEF) after MI was between 42% and 54%, which may in clinical settings not represent the correct target population with moderate to severe left ventricular dysfunction 8 .…”

“…Unfortunately, in those studies on porcine and sheep models in which treatment success of cell-based therapies for (experimentally induced) MI was assessed using MRI, temporary occlusion of the left anterior descending (LAD) artery was (except of one study that showed no success 26 ) restricted to 60 min 27,28 or 90 min 29,30 . As a result, in most of these studies 27,28,30 the left ventricular ejection fraction (LVEF) after MI was between 42% and 54%, which may in clinical settings not represent the correct target population with moderate to severe left ventricular dysfunction 8 . Furthermore, cells were delivered immediately after experimental induction of MI in twelve out of the 16 preclinical studies on cell-based therapy for MI using porcine and sheep animal models summarized in Supplementary Table 1.…”