Mesenchymal and Pluripotent Stem Cell‐Based Strategies for Cardiac Regeneration: Mechanisms, Challenges, and Future Directions

ABSTRACT Cardiovascular diseases (CVDs) remain the predominant cause of morbidity and mortality worldwide, with limited curative treatment options for advanced heart failure (HF). While pharmacological and surgical interventions have improved survival, they often fail to regenerate damaged myocardial tissue. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality in regenerative medicine, particularly for cardiac repair. This review highlights the role of MSCs in addressing the unmet clinical need for myocardial regeneration, focusing on their biological characteristics, mechanisms of action, and therapeutic applications in various CVDs. MSCs, derived from bone marrow or adipose tissue, exhibit immunomodulatory, anti‐fibrotic, and pro‐angiogenic properties that facilitate cardiac tissue repair. Their ability to be used in an allogeneic, off‐the‐shelf format offers practical advantages for large‐scale clinical use. However, several challenges, including poor survival post‐transplantation, inter‐source variability, and complex interactions with the ischemic microenvironment, must be addressed to maximize therapeutic efficacy. Emerging technologies such as gene editing, exosome‐based delivery, tissue engineering, and 3D bioprinting offer promising strategies to enhance MSC therapy. This review concludes by outlining future directions for standardization, clinical translation, and optimization of MSC‐based cardiac regenerative therapies.