Background: Human-induced pluripotent stem cells (hiPSCs) with normal or upregulated levels of CCND2 expression were differentiated into cardiomyocytes (CCND2WTCMs or CCND2OECMs, respectively) and injected into infarcted pig hearts. Methods: Acute myocardial infarction (AMI) was induced via a 60-minute occlusion of the left-anterior descending coronary artery. Immediately after reperfusion, CCND2WTCMs or CCND2OECMs (3×107 cells each), or an equivalent volume of the delivery vehicle was injected around the infarct border zone area. Results: The number of the engrafted CCND2OECMs exceeded that of the engrafted CCND2WTCMs from 6 to 8-fold, rising from 1 week to 4 weeks post-implantation. In contrast to the treatment with the CCND2WTCMs or the delivery vehicle, the administration of CCND2OECM was associated with significantly improved left-ventricular function, as revealed by magnetic resonance imaging (MRI). This correlated with the reduction of infarct size, fibrosis, ventricular hypertrophy, CM apoptosis, and the increase of vascular density and arterial density, as per the histological analysis of the treated hearts. Expression of the cell proliferation markers (e.g., Ki67, phosphorylated histone 3 [PH3] and Aurora Kinase B [Aurora B]) was also significantly upregulated in the recipient CMs from the CCND2OECM-treated than from the CCND2WTCM-treated pigs. The cell proliferation rate and the hypoxia tolerance measured in cultured hiPSC-CMs were significantly greater after their treatment with exosomes isolated from the CCND2OECMs (CCND2OEExos) than from the CCND2WTCMs (CCND2WTExos). As demonstrated by our study, CCND2OEExos can also promote the proliferation activity of postnatal rat and adult mouse cardiomyocytes. A bulk miRNA sequencing analysis of CCND2OEExos vs. CCND2WTExos identified 206 and 91 miRNAs that were significantly upand down-regulated, respectively. Gene ontology (GO) enrichment analysis identified significant differences in the expression profiles of miRNAs from various functional categories and pathways, including miRNAs implicated in cell-cycle checkpoints (G2/M and G1/S transitions), or the mechanism of cytokinesis. Conclusions: We have demonstrated that an enhanced potency of the CCND2OECMs promoted myocyte proliferation in both grafts and the recipient tissue in a large mammal acute myocardial infarction (AMI) model. These results suggest that the CCND2OECMs transplantation may be a potential therapeutic strategy for the repair of infarcted hearts.