Stem cell-based regenerative therapies for non-ischemic cardiomyopathy: mechanistic insights, clinical evidence, and future directions.

Non-ischemic cardiomyopathy (NICM) includes a wide spectrum of myocardial disorders that result in ventricular dysfunction in the absence of significant coronary artery disease. The currently available treatments are primarily palliative in nature as they are not able to restore damaged cardiomyocytes or reverse structural damage. Stem cell-based regenerative methods show a potential therapeutic solution as instead of providing symptomatic benefits they are aimed at targeting the underlying cause. It has been observed in preclinical studies that the different types of stem cells act through immunomodulation, paracrine signaling, antifibrotic effects, and promoting angiogenesis rather than through direct action on cardiomyocytes. The improvement in left ventricular ejection fraction, functional capacity, and quality of life parameters observed in early-phase clinical trials for NICM show inconsistent results primarily due to heterogeneity in study design, type of stem cells, delivery methods, and patient selection. The main limitations include poor engraftment, heterogeneity of outcomes, and long-term safety concerns, particularly arrhythmogenic potential and tumorigenesis in pluripotent cell-based approaches. The advancements in genetic engineering, extracellular vesicle therapy, and combined cell-gene strategies are expanding the horizons of therapeutic potential of stem cells. This review synthesizes current evidence, highlights translational challenges, and explores emerging directions, including biomaterial-assisted delivery and precision medicine-based patient stratification, which may enable stem cell therapies to become a viable adjunct in managing NICM.