Human induced pluripotent stem cell-derived cardiomyocyte patch enhances cardiac regeneration in a J2N-k hamster model of dilated cardiomyopathy

Introduction Dilated cardiomyopathy (DCM) is a major cause of heart failure with limited therapeutic options beyond heart transplantation. This study aimed to evaluated the therapeutic potential of human induced pluripotent stem cell-derived cardiomyocyte (hiPS-CM) patch transplantation in a genetic DCM model. Methods hiPS-CM patches were transplanted onto the left ventricular surface of adult J2N-k hamsters with DCM. Cardiac function, survival, and histological evaluation were assessed. Single-nucleus RNA sequencing using left ventricular myocardium was performed to investigate cell-type-specific transcriptional alteration associated with treatment. Results hiPS-CM patch transplantation preserved cardiac function [left ventricular ejection fraction, 41.2 (38.9 – 42.8) vs. 43.4 (40.5 – 44.6) %, P = 0.07], improved survival [Hazrod ratio 0.39 (95% confidence interval 0.16 – 0.63), P < 0.05], reduced myocardial fibrosis [fibrous area, 10.2 (9.4 – 12.1) vs. 14.1 (13.1 – 18.3) %, P < 0.05], and increased capillary density [CD-31 positive cells cout, 373.2 (336.4 – 441.3) vs. 210.7 (157.4 – 232.3) cells/mm 3 , P < 0.05] in J2N-k hamsters compared with controls. Transcriptomic analysis revealed regenerative shifts across multiple cell types, including activation of cardiac transcription factors (MEF2C, GATA4, NKX2-5), upregulation of angiogenesis-related pathways (ERK1/2 cascade, KLF4, ETS1, GATA2), and modulation of pro-fibrotic signaling (SMAD3, STAT3, NF-κB). Conclusions hiPS-CM patch transplantation exerts therapeutic effects through multicellular mechanisms, including enhanced angiogenesis, improved myocardial microenvironment, and modulation of fibrosis. These findings support the feasibility of hiPS-CM patch therapy as a regenerative strategy for end-stage DCM and provide mechanistic insights into its therapeutic action.