Ischemic Heart Disease (IHD) remains the world’s leading cause of morbidity and mortality. Despite advances in medical and surgical interventions, many patients still experience irreversible myocardial damage due to inadequate regeneration of cardiac tissue. This limitation has driven the global scientific community toward cell-based regenerative therapies, particularly mesenchymal stem cell (MSC) therapy, as a novel strategy to restore cardiac function.
MSC stem cell therapy is designed to repair ischemic myocardial tissue, enhance angiogenesis, and modulate inflammation targeting both structural and functional heart recovery.
Discovery and Characteristics of Mesenchymal Stem Cells
The discovery of MSC stem cell dates back to the 1960s when Friedenstein identified fibroblast-like, colony-forming cells from bone marrow with the ability to differentiate into osteocytes, chondrocytes, and adipocytes.
In 2006, the International Society for Cellular Therapy (ISCT) defined the minimal criteria for human MSC stem cell:
- Plastic adherence under standard culture conditions.
- Positive for CD105, CD73, CD90 and negative for CD45, CD34, CD14/CD11b, CD19, and HLA-DR.
- Capability to differentiate into bone, fat, and cartilage lineages.
MSC stem cell can be isolated from various tissues, including bone marrow, adipose tissue, umbilical cord, placenta, and dental pulp, providing both autologous and allogeneic therapeutic options.
Mechanisms of MSC-Mediated Cardiac Repair
The review identifies four primary mechanisms through which MSC stem cell promote cardiac regeneration:
- Engraftment and Differentiation:
MSC stem cell can differentiate into cardiomyocyte-like or endothelial cells, replacing necrotic myocardium. - Paracrine Signaling:
MSC stem cell secrete growth factors such as VEGF, HGF, IGF-1, and angiopoietin, enhancing angiogenesis and cell survival. - Activation of Endogenous Cardiac Stem Cells:
MSC stem cell stimulate native cardiac progenitor cells (CPCs) via paracrine mediators, promoting tissue repair. - Neovascularization and Immunomodulation:
MSC stem cell reduce fibrosis, suppress immune overactivation, and promote the growth of new blood vessels in ischemic myocardium.
The combination of these processes prevents pathological remodeling and improves contractile strength, reducing infarct size and restoring perfusion.
Paracrine and Exosome-Mediated Effects
The paracrine effect is considered the dominant mechanism behind MSC stem cell therapy.
MSC stem cell release a “secretome” rich in cytokines, growth factors, and extracellular vesicles (EVs) that exert anti-apoptotic, anti-fibrotic, and angiogenic effects.
Key factors include:
- VEGF, HGF, IL-6, and PLGF – enhance vascular growth and cell survival.
- Matrix metalloproteinases (MMP-2, MMP-9) – remodel scar tissue.
- Exosomes containing microRNAs (miR-22, miR-221) – suppress apoptosis and improve cardiac recovery.
Exosome-based therapy, often called “cell-free stem cell therapy,” is emerging as an innovative approach that may replicate MSC benefits without cell transplantation.
Immunomodulatory and Anti-Inflammatory Effects
MSC stem cell play a key role in modulating both the innate and adaptive immune systems post-injury.
They secrete immunoregulatory molecules such as:
- Transforming growth factor-β (TGF-β)
- Prostaglandin E2 (PGE2)
- Interleukin-10 (IL-10)
- TNF-stimulated gene-6 (TSG-6)
These mediators suppress T-cell proliferation, inhibit natural killer (NK) cell activation, and reduce inflammatory cytokine production, thereby creating a microenvironment conducive to cardiac healing.
Evidence from Preclinical Studies
Animal studies in rodents, rabbits, and pigs demonstrated that MSC stem cell significantly improve left ventricular ejection fraction (LVEF), reduce infarct size, and enhance angiogenesis:
- BM-MSCs and ADSCs promoted VEGF-mediated neovascularization.
- Umbilical cord–derived MSCs (UC-MSCs) reduced fibrosis and inflammation via downregulation of TNF-α and ERK1/2 signaling.
- Porcine models confirmed that intracoronary and transendocardial MSC injections increased contractility and reduced scar formation.
Clinical Trials in Ischemic Heart Disease
Multiple phase I–III clinical trials validate MSC safety and efficacy in both acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy (ICM):
- POSEIDON Trial (NCT01087996):
Both autologous and allogeneic BM-MSC stem cell improved left ventricular function, reduced scar size by ~33%, and enhanced quality of life after 13 months. - TRIDENT Trial (NCT02013674):
Compared low (20M) vs. high (100M) allogeneic BM-MSC doses; higher dose improved ejection fraction by 3.7%. - PROMETHEUS and TAC-HFT Trials:
Demonstrated improved myocardial perfusion and reduced infarct mass through transendocardial and intramyocardial injections. - PRECISE Study:
Adipose-derived MSCs (AD-MSCs) improved myocardial mass and perfusion in no-option patients with ischemic cardiomyopathy. - Ongoing Trials:
UC-MSC Heart (NCT02439541) evaluates umbilical cord–derived MSC stem cell, and CONCERT-HF (NCT02501811)investigates combined MSC and cardiac stem cell therapy, showing synergistic benefits.
Optimal Administration and Dosage
Among tested delivery routes intravenous, intracoronary, transendocardial, and intramyocardial the transendocardial route showed superior efficacy, improving LVEF and reducing scar tissue most effectively. An optimal cell dose between 20–100 million MSCs demonstrated consistent safety and functional benefit.
Conclusion
The reviewed literature confirms that mesenchymal stem cell therapy is a safe, feasible, and promising regenerative approach for ischemic heart disease.
Through mechanisms including paracrine signaling, exosome release, angiogenesis, and immunomodulation, MSC stem cell significantly enhance cardiac recovery and prevent further remodeling.
While challenges such as cell survival, standardized dosing, and long-term outcomes remain, ongoing clinical trials continue to demonstrate encouraging results bringing MSC therapy closer to clinical reality as a next-generation treatment for heart failure and myocardial infarction.
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“Mesenchymal Stem Cell (MSCs) Therapy for Ischemic Heart Disease: A Promising Frontier” (Global Heart, 2022)