Comparative Efficacy of Intracoronary Allogeneic Mesenchymal Stem Cells and Cardiosphere-Derived Cells in Swine with Hibernating Myocardium

Abstract

Rationale Allogeneic bone marrow-derived mesenchymal stem cells (MSCs) and cardiosphere-derived cells (CDCs) have each entered clinical trials but a direct comparison of these cell types has not been performed in a large animal model of hibernating myocardium. Objective Using completely blinded methodology, compare the efficacy of global intracoronary allogeneic MSCs (icMSCs, ~35×106) and CDCs (icCDCs, ~35×106) vs. vehicle in cyclosporine-immunosuppressed swine with a chronic LAD stenosis (n=26). Methods and Results Studies began 3-months after instrumentation when wall-thickening (%WT) was reduced (LAD%WT 38±11% (mean ± SD) vs. 83±26% in remote, p<0.01) and similar among groups. Four-weeks after treatment, LAD%WT increased similarly following icCDCs and icMSCs, while it remained depressed in vehicle-treated controls (icMSCs: 51±13%; icCDCs: 51±17%; vehicle: 34±3%, treatments p<0.05 vs. vehicle). There was no change in myocardial perfusion. Both icMSCs and icCDCs increased LAD myocyte nuclear density (icMSCs: 1601±279 nuclei/mm2, icCDCs: 1569±294 nuclei/mm2, vehicle: 973±181 nuclei/mm2, treatments p<0.05 vs. vehicle) and reduced myocyte diameter (icMSCs: 16.4±1.5 μm, icCDCs: 16.8±1.2 μm, vehicle: 20.2±3.7 μm, treatments p<0.05 vs. vehicle) to the same extent. Similar changes in myocyte nuclear density and diameter were observed in the remote region of cell-treated animals. Cell fate analysis using Y-FISH demonstrated rare cells from sex-mismatched donors. Conclusions Allogeneic icMSCs and icCDCs exhibit comparable therapeutic efficacy in a large animal model of hibernating myocardium. Both cell types produced equivalent increases in regional function and stimulated myocyte regeneration in ischemic and remote myocardium. The activation of endogenous myocyte proliferation and regression of myocyte cellular hypertrophy support a common mechanism of cardiac repair.

Inhibiting Extracellular Vesicle Release from Human Cardiosphere Derived Cells with Lentiviral Knockdown of nSMase2 Differentially Effects Proliferation and Apoptosis in Cardiomyocytes, Fibroblasts and Endothelial Cells In Vitro

“…Nevertheless, endothelial cells cocultured with control Scr CDCs showed increased migration and tube formation in an in vitro angiogenesis assay which was blocked by inhibiting exosome release with knockdown of nSMase2. This stimulation of angiogenic activity is consistent with our previous in vivo results showing increased capillary density throughout the heart following intracoronary injection of CDCs in swine with hibernating myocardium[1, 2]. It is also consistent with the increase in capillary density found after focal injection of purified CDC derived exosomes into the border zone of a murine infarction by others [15].…”

“…This passage also corresponds to the passage of CDCs transplanted into our porcine model of hibernating myocardium [1, 2]. As a control, we also isolated exosomes from normal human dermal fibroblasts (NHDF) at P4.…”

“…Interestingly, regardless of the platform used, there appears to be a disproportionate benefit of cellular therapy on functional improvement in relation to the number of injected stem cells that remain in the heart or transdifferentiate into cardiac myocytes in large animal models of cardiovascular disease [1–5]. This has given rise to the notion that many therapies work through a paracrine signaling mechanism that stimulates endogenous myocyte and capillary formation while at the same time, inhibiting fibrosis [6–9].…”

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

“…Nonetheless, genetic lineage-fate mapping studies show that, under the proper conditions, endogenous CPCs (145,348,368), and to a smaller extent BMCs (289,396) and MSCs (60,144,290) produce new cardiomyocytes in the postnatal heart, albeit at a functionally insignificant level. Paradoxically, compared with ESC/iPSC-based strategies, engraftment of MSCs and CPCs is lower but leads to significant heart regeneration and recovery of heart function (62,97,119,137,143,144,147,174,175,228,229,284,290,321,322,385). Ex vivo tissue engineering approaches, whereby MSCs are combined or fused with adult human CPCs (175, 291,392), ESC/iPSC-derived CPCs (42), endothelial progenitors (417), and possibly neurons (224,389) may improve long-term engraftment and/or differentiation of the adult cell grafts and therefore lead to a meaningful level of myocardial regeneration and functional recovery.…”

Widespread Intracoronary Cardiopoietic Cell Infusion

“…While this requires transient aortic occlusion and is technically challenging in the rodent heart, it is straightforward to accomplish in humans and large animals by direct intracoronary infusion. Suzuki demonstrated that continuous intracoronary infusion was efficacious without cessation of coronary flow and stimulated myocyte proliferation throughout the diseased but not normal heart after widespread intracoronary MSC and CDC administration to swine with hibernating myocardium 10, 11, 13 . Others have shown that transient occlusion or “stop flow” is not required for CSC or CDC uptake and demonstrated functional efficacy of CDCs administered without cessation of flow following acute myocardial infarction 14, 15 .…”