treatment was five to seven days post-AMI.
Mesenchymal SC Treatments for Heart Disease
Non-hematopoietic SCs in adult BM are called stromal or mesenchymal cells. Mesenchymal stem cells (MSCs) have the capacity for self-renewal and multi-lineage differentiation to generate bone, cartilage, fibrous connective tissue, even myocytes. Although MSCs represent only 1 percent of nucleated cells in BM, in vitro culture expansion can successfully generate sufficient cells for timely therapeutic potential, and harvest of MSCs from other sources, such as adipose tissue and even allogenic sources, is also possible. To treat heart disease, MSCs demonstrate promise to graft into a variety of cell types, including vascular smooth muscle and endothelial, which improve cardiovascular function through neovascularization, secretion of growth factors, cytokines, and other signaling molecules. Transdifferention has been shown to occur both in vitro to cardiomyocytes as well as in vivo to cardiomyocytes when among naïve cardiomyocytes.
Several MSC-therapy clinical trials, including the TAC-HFT trial at the University of Miami, also found results of improved LV function, as well as reverse ischemic remodeling and decreased post-AMI size. The POSEIDON trial at the University of Miami established MSCs’ autologous and allogenic safety and efficacy in treatment of early-stage IHD, and found that patients who received low-dose treatment of MSCs (20 million cells) presented with the most favorable reductions in LV volume and increased EF. Clinical trials for autologous adipose-derived MSCs have not begun in the United States but show promise internationally, such as in the APOLLO trial.
Embryonic Stem Cell Treatments for Heart Disease
Human embryonic stem cells (hESCs) are omnipotent or pluripotent cells derived from pre-implantation-stage embryos. These cells have been intensively investigated for their potential use in cardiac regeneration, and several pre-clinical trials have found that hESCs differentiate into contractile cardiomyocytes in vitro. Clinical application of hESCs is controversial due to ethical issues, immunological incompatibility, and risk of teratoma formation. As of 2014, no U.S. clinical trials with hECSs have begun.
Induced Pluripotent SC Treatments for Heart Disease
As late as 2006, Shinya Yamanaka discovered that adult somatic cells can be induced by pluripotency transcription factors to form induced pluripotent stem cells (iPSCs). iPSCs have the potential to be therapeutically useful, but many technical issues must first be resolved that will require a better understanding of their biology. As of 2014, no U.S. clinical trials with iPSCs have begun.
Cardiac SC and Cardiosphere-Derived Treatments for Heart Disease
The adult heart contains cardiac stem cells (CSCs) that express the unique surface receptor tyrosine kinase c-kit as well as other markers, such as Sca-1, and Isl-1. These cells are self-renewing, clonogenic, and multipotent, which allows them to differentiate into myocytes, vascular smooth muscle, and endothelial cells. CSCs are harvested via a minimally invasive biopsy or during cardiac surgery, isolated from others cells by markers, expanded in vitro, and can be frozen for subsequent use.
The first clinical trial to publish results on CSC treatment in heart disease was the SCIPIO Phase 1 trial, in which CSCs were harvested from right atrial appendages during coronary artery bypass graft (CABG) and eventually readministered via intracoronary injection. After one year, LVEF increased by 12.3 percent and post-AMI size decreased by 30 percent.
Another SCIPIO Phase I trial at the University of Louisville that analyzed results through cardiac magnetic resonance (CMR) found that at one year LVEF increased by 41.2 percent, global and regional LV function improved, post-AMI size decreased by 30 percent, and viable tissue increased.
Cardiosphere-derived SCs (CDCs) are clusters of core c-kit-positive SCs, differentiating cells, and outer MSCs that form from myocardial tissue under appropriate culture conditions. Studies importantly demonstrate that CDCs express connexin-43 and form gap junctions, which allows electrical coupling.
The 2012 CADUCEUS trial at Cedars-Sinai Heart Institute found via CMR that autolo-gous endomyocardial-CDCs 1.5 to three months post-AMI resulted in reduction of post-AMI size and an increase in both viable cardiac mass and regional contractility. Although this trial did not demonstrate significant changes in LVEF, recent studies suggest the importance of SC therapies would be missed if EF were the sole endpoint, as EF is dependent upon non-cardiac factors, such as the neurohormonal state.
Measures of LV remodeling, such as decrease in chamber volume, sphericity index, and reduction of post-AMI size prove more clinically meaningful to elucidate SC treatment efficacy.
Future Directions
Several trials have tested optimal techniques of SC administration. Some demonstrate that intravenous administration leads to SC-entrapment in the liver and lungs. Intracoronary infusion is the most frequently used technique; however, it is associated with only 1–3 percent myocardial retention. Direct intramyocardial injection of SCs has been shown to result in higher myocardial cell retention without compromising coronary flow. However, preclinical and clinical studies suggest that more than just cells are necessary to mend a diseased heart—the framework to support cells is also crucial. Without reestablishment of adequate cardiac vascularization and extracellular matrix, SCs are unlikely to survive. Future clinical trials plan to identify optimal SCs that permit treatment without immune suppression, optimal timing for chemoattraction of SC to damaged cardiac tissue, and optimal propagation in the myocardium.
Krishna S. Vyas
Tara Shrout
University of Kentucky College of Medicine
See Also: Heart: Cell Types Composing the Tissue; Heart: Current Research on Isolation or Production of Therapeutic Cells; Heart: Development and Regeneration Potential; Heart: Existing or Potential Regenerative Medicine Strategies; Heart: Major Pathologies; Heart: Stem and Progenitor Cells in Adults; Heart: Tissue Function; Heart Disease.
Further Readings
Beltrami, A. P., L. Barlucchi, D. Torella, M. Baker, et al. “Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration.” Cell, v.114/6 (2003).
Bolli, R., A. R. Chugh, D. D’Amario, J. H. Loughran, et al. “Cardiac Stem Cells in Patients With Ischaemic Cardiomyopathy (SCIPIO): Initial Results of a Randomised Phase 1 Trial.” Lancet, v.26/378 (2011).
Chen, S. L., W. W. Fang, F. Ye, Y. H. Liu, et al. “Effect on Left Ventricular Function of Intracoronary Transplantation of Autologous Bone Marrow Mesenchymal Stem Cell in Patients With Acute Myocardial Infarction.” American Journal of Cardiology, v.94/1 (2004).
Chugh, A.R., G. M. Beache, J. H. Loughran, N. Mewton, et al. “Administration of Cardiac Stem Cells in Patients With Ischemic Cardiomyopathy: The SCIPIO Trial: Surgical Aspects and Interim Analysis of Myocardial Function and Viability by Magnetic Resonance.” Circulation, v.126/11suppl1 (2012).
Duckers, H.J., J. Houtgraaf, C. Hehrlein, J. Schofer, et al. “Final Results of a Phase IIa, Randomised, Open-Label Trial to Evaluate the Percutaneous Intramyocardial Transplantation of Autologous Skeletal Myoblasts in Congestive Heart Failure Patients: The SEISMIC Trial.” EuroIntervention, v.6.7 (2011).
Hare, J. M., J. H. Traverse, T., D. Henry, N. Dib, et al. “A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation
