Cell-Based Therapies for Cardiac and Vascular Regeneration in Cardiovascular Disease: Recent Advances, Translational Barriers, and Future Directions

Cardiovascular diseases (CVDs) remain the foremost cause of death globally, responsible for 19.2 million deaths and 437 million disability-adjusted life years in 2023, with prevalent cases having more than doubled since 1990. No approved therapy restores myocardium lost to infarction. The adult heart replaces cardiomyocytes at approximately 1% per year in young adults, declining to about 0.45% per year with ageing, far below what is needed to recover the more than one billion cells destroyed by a large myocardial infarction. Cell-based regenerative strategies have been investigated for more than two decades, encompassing bone marrow mononuclear cells (BM-MNCs), mesenchymal stromal cells (MSCs), cardiac progenitor cells, cardiosphere-derived cells (CDCs), skeletal myoblasts, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Safety has been consistent. Efficacy has been modest and variable: the CADUCEUS trial demonstrated scar mass reduction with CDCs without proportionate ejection fraction improvement; the Phase 1/2 POSEIDON trial confirmed MSC safety in 30 patients; and the Phase 3 DREAM-HF trial, enrolling 537 patients, failed its primary endpoint (HR 1.2, p = 0.406). Mechanistic work has established that transplanted cells engraft poorly and exert their benefit principally through paracrine signalling mediated by secreted extracellular vesicles and exosomes carrying microRNAs, trophic factors, and immunomodulatory proteins. For iPSC-CMs, electrophysiological immaturity and arrhythmogenic risk in primate models remain unresolved barriers. Emerging strategies include CRISPR-engineered hypoimmune iPSC lines, bioengineered cardiac patches, injectable hydrogel scaffolds, and engineered exosome platforms. This review provides a comprehensive synthesis of preclinical and clinical evidence, examines translational barriers, and identifies the scientific and regulatory priorities required before these therapies can enter routine clinical practice.