Intracoronary Delivery of Human Mesenchymal/Stromal Stem Cells: Insights from Coronary Microcirculation Invasive Assessment in a Swine Model

Abstract

BackgroundMesenchymal stem/stromal cells have unique properties favorable to their use in clinical practice and have been studied for cardiac repair. However, these cells are larger than coronary microvessels and there is controversy about the risk of embolization and microinfarctions, which could jeopardize the safety and efficacy of intracoronary route for their delivery. The index of microcirculatory resistance (IMR) is an invasive method for quantitatively assessing the coronary microcirculation status.ObjectivesTo examine heart microcirculation after intracoronary injection of mesenchymal stem/stromal cells with the index of microcirculatory resistance.MethodsHealthy swine were randomized to receive by intracoronary route either 30x106 MSC or the same solution with no cells (1% human albumin/PBS) (placebo). Blinded operators took coronary pressure and flow measurements, prior to intracoronary infusion and at 5 and 30 minutes post-delivery. Coronary flow reserve (CFR) and the IMR were compared between groups.ResultsCFR and IMR were done with a variance within the 3 transit time measurements of 6% at rest and 11% at maximal hyperemia. After intracoronary infusion there were no significant differences in CFR. The IMR was significantly higher in MSC-injected animals (at 30 minutes, 14.2U vs. 8.8U, p = 0.02) and intragroup analysis showed a significant increase of 112% from baseline to 30 minutes after cell infusion, although no electrocardiographic changes or clinical deterioration were noted.ConclusionOverall, this study provides definitive evidence of microcirculatory disruption upon intracoronary administration of mesenchymal stem/stromal cells, in a large animal model closely resembling human cardiac physiology, function and anatomy.

Lower retention after retrograde coronary venous infusion compared with intracoronary infusion of mesenchymal stromal cells in the infarcted porcine myocardium

“…Because retention of cells in the heart is calculated as a percentage of the total administered cell dose in case of in vivo analysis, it is probable that a higher cell dose would not result in a higher retention rate. However, it is known that infusion of larger volumes of cells (30×10 6 –50×10 6 ) via the IC route can result in a higher index of microcirculatory resistance 17 18…”

Acellular Urethra Bioscaffold: Decellularization of Whole Urethras for Tissue Engineering Applications

“…Urethras (n = 17: female, n = 9 and male, n = 8) were obtained from cadaveric female Yorkshire piglets (Group 1: 8.2 ± 3.8 Kg, n = 11) and Duroc male and F1 Large White X Landrace pigs (Group 2: 31 ± 3.9 Kg, n = 6). Cadaveric animals were provided from experimental studies approved by the Animal Care and Use Committee (ACUC) of Wake Forest University Health Sciences in USA and Direcção Geral de Alimentação e Veterinária (DGAV) in Portugal 25 . Animal handling and dissections were performed in accordance with guidelines and regulations of ACUC and DGAV.…”

Persistence and proliferation of human mesenchymal stromal cells in the right ventricular myocardium after intracoronary injection in a large animal model of pulmonary hypertension

“…This approach could allow the cells to remain in the cardiac tissue long enough to adhere to endothelium and migrate into the extravascular space. Balloon occlusion could also provide enough transient ischemia to allow for a mild injury that would “condition” the local environment promoting donor cell survival and retention [8,9]. Another consideration is that only a subset of hMSCs retain long-term engraftment capability.…”

“…Several studies support the ability of these MSCs either to repair or regenerate damaged myocardium [3–5], although their long-term durability in tissue is controversial [6,7]. The safety of MSC delivery to the left ventricle after acute myocardial infarction has also been established, via intracoronary, intramyocardial, or intravenous routes of administration [8,9]. Preclinical studies have also suggested that cell therapy with MSCs has substantial potential to treat right ventricular (RV) remodeling and dysfunction resulting from pulmonary hypertension (PH) and other diseases of the lung [10,11].…”