Intracoronary Delivery of Porcine Cardiac Progenitor Cells Overexpressing IGF-1 and HGF in a Pig Model of Sub-Acute Myocardial Infarction

Abstract

Human cardiac progenitor cells (hCPC) are considered a good candidate in cell therapy for ischemic heart disease, demonstrating capacity to improve functional recovery after myocardial infarction (MI), both in small and large preclinical animal models. However, improvements are required in terms of cell engraftment and efficacy. Based on previously published reports, insulin-growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) have demonstrated substantial cardioprotective, repair and regeneration activities, so they are good candidates to be evaluated in large animal model of MI. We have validated porcine cardiac progenitor cells (pCPC) and lentiviral vectors to overexpress IGF-1 (co-expressing eGFP) and HGF (co-expressing mCherry). pCPC were transduced and IGF1-eGFPpos and HGF-mCherrypos populations were purified by cell sorting and further expanded. Overexpression of IGF-1 has a limited impact on pCPC expression profile, whereas results indicated that pCPC-HGF-mCherry cultures could be counter selecting high expresser cells. In addition, pCPC-IGF1-eGFP showed a higher cardiogenic response, evaluated in co-cultures with decellularized extracellular matrix, compared with native pCPC or pCPC-HGF-mCherry. In vivo intracoronary co-administration of pCPC-IGF1-eGFP and pCPC-HFG-mCherry (1:1; 40 × 106/animal), one week after the induction of an MI model in swine, revealed no significant improvement in cardiac function.

Intracoronary Administration of Microencapsulated HGF in a Reperfused Myocardial Infarction Swine Model

“…Our results differ from those reported by Ellison et al [ 13 ], where a significant improvement of all cMR-analyzed parameters was found in all groups treated with growth factors. This obvious difference in results may be associated with the use of a combination of HGF and IGF-1 in their study, although not all studies using these combinations have reported positive results [ 45 ].…”

“…Nevertheless, they point out the need to develop release systems for this therapy [ 11 ]. While several published works point to a clear benefit of administering HGF in this setting [ 9 , 13 , 50 , 53 ], there are also examples of previous studies that obtained unexpected (negative or neutral) results using growth factors therapies, as a recent published paper exposes [ 45 ]. In this study, the IC co-administration one week after MI induction of porcine Cardiac Progenitor Cells (pCPC) overexpressing IGF-1 (pCPC-IGF-1) and HGF (pCPC-HGF) did not improve cardiac function.…”

“…This previous work demonstrated that IGF-1 could have superior potential to promote cardiac differentiation than HGF, as also seen when using encapsulated IGF-1 [ 17 ]. It could be associated with a lower stability of the HGF protein compared to the IGF-1 [ 45 ]. Therefore, we expected that HGF microencapsulation could provide stability to the growth factor and, as seen with IGF-1, its administration two days after MI induction (between the early inflammation and the later fibrosis) could be effective and would improve cardiac function.…”

Transplantation of Fibroblast Sheets with Blood Mononuclear Cell Culture Exerts Cardioprotective Effects by Enhancing Anti-Inflammation and Vasculogenic Potential in Rat Experimental Autoimmune Myocarditis Model

“…The increases in QQMNCs versus PBMNCs were 4.12-fold for Vegf-a ( p < 0.01) and 56.08 for Vegf-b ( p < 0.01). The expression levels of cardioprotective factors, including Vegf-b [ 32 ], hepatocyte growth factor ( Hgf ) [ 33 ], and insulin-like growth factor 1( Igf -1) [ 34 ], were higher in QQMNCs than in PBMNCs. The increases in QQMNCs versus PBMNCs were 3.58-fold for Hgf and 2.34-fold for Igf-1 .…”

Optimal transplantation strategy using human induced pluripotent stem cell‐derived cardiomyocytes for acute myocardial infarction in nonhuman primates

“…Intravenous transplantation is almost noninvasive; however, the majority of cells may migrate to other organs and few may remain in the infarct site 7 . For patients undergoing percutaneous infarct‐associated arterial revascularization after acute MI, infusion of transplanted cells through intracoronary injection is a feasible method; however, most of the transplanted cells are cleared in a short period of time, 7 and the results of efficacy and safety studies are inconsistent 8–11 . One cause of these issues is that the transplanted cells are not mature enough, and the other is that the route of transplantation impacts the healing outcome.…”