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

Abstract

Background aims: In this study, we demonstrate long-term persistence of human mesenchymal stromal cells (hMSCs) after intracoronary injection in a large animal model of pulmonary hypertension (PH).

Methods: Commercially available placenta-derived hMSCs were used. Experiments were conducted on 14 female Yorkshire swine. Four animals served as controls, and 10 underwent pulmonary vein (PV) banding. After 12 ± 2 weeks, PH and PV dysfunction were confirmed by right heart catheterization and cardiac magnetic resonance imaging. hMSCs were injected in the marginal branch of the right coronary artery. Tissues were harvested 6, 9 or 24 days after infusion.

Results: After 12 ± 2 weeks after PV banding, all subjects had increased mean pulmonary artery pressure (13.6 ± 3.6 versus 30.8 ± 4.5 mm Hg, P < 0.007) and a decrease in right ventricular ejection fraction from 51.7 ± 5.7% versus 30.5 ± 11.3% (P = 0.003). Intracoronary injection of hMSCs was well tolerated. Up to 24 days after hMSC injection, immunohistochemistry revealed extravascular viable human CD105⁺ mononuclear cells in the right ventricle (RV) that were Ki67⁺. This was confirmed by fluorescence in situ hybridization. CD45⁺ porcine inflammatory cells were identified, commonly seen adjacent to areas of healing microscopic infarction that likely dated to the time of the original hMSC injection. Anti-CD31 staining produced strong signals in areas of injected hMSCs. Immunohistochemistry staining for vascular cell adhesion molecule-1 showed upregulation in the clusters, where mononuclear cells were located.

Conclusions: hMSCs injected via intracoronary infusion survived up to 24 days and demonstrated proliferative capacity. hMSCs can persist long term in the RV and are potential cell source for tissue repair in RV dysfunction.

Keywords: differentiation; human mesenchymal stromal cells; intracoronary injection; pulmonary hypertension; right ventricular remodeling.