Abstract
Heart failure (HF) is a global epidemic with a rising burden on individuals and healthcare systems. Advanced HF is characterized by severe symptoms at rest and marked limitations in physical activity. Stem cell therapies potentially address the limitations of current conventional treatments by reversing damage to cardiac tissue via their unique capacity for self-renewal and multilineage differentiation. This article summarized the mechanism of action and methods for each stem cell approach and provided a detailed summary of associated clinical trials focusing on efficacy, safety profiles, and future directions. We conducted a systematic review with a comprehensive search from 2014 to 2024 using databases such as PubMed, SCOPUS, and Google Scholar. Articles that met the inclusion criteria were selected by abstract review and subsequent assessment of the full text. This review analyzes 27 clinical trials investigating stem cell-based therapies for advanced HF across different clinical phases (Phases I, II, and III) conducted between 2014 and 2024. These approaches include adult stem cells (ASCs) such as cardiac stem cells (CSCs), cardiosphere-derived cells (CDCs), cardiac progenitor cells (CPCs), unfractionated bone marrow-derived mononuclear cells (BMMNCs), mesenchymal stem cells (MSCs) and pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs, induced pluripotent stem cells (iPSCs). While the exact mechanisms through which stem cells exert their therapeutic effects in advanced HF remain under investigation, recent attention has shifted toward the paracrine signaling effects of injected cells. All approaches have demonstrated clinically acceptable safety profiles; however, their efficacy varies and has yet to be conclusively confirmed. MSC-based therapy is the most widely used among the different cell choices and has consistently exhibited promising outcomes. Although ESCs are promising for heart regeneration, their use is significantly limited by ethical issues that advancements in iPSCs may potentially address. With further efficacy validation, especially in phase III clinical trials, stem cell therapies hold promising potential for clinical application in advanced HF.