Abstract
The translation of cardiac cell therapies into the clinic has advanced significantly since the last dedicated issue in Cell Transplantation in 2008. This special issue of Cell Transplantation is dedicated to providing new information related to the multiple novel biologics under investigation in clinical trials, but more importantly the basic mechanisms and their interactions that play a role at the cellular and tissue level. Despite over 15 years of investigation, no cell therapies are approved for use in cardiovascular disease. As the field of cardiac biologics matures, comparison and evaluation of cells, genes, and matrices, as well as with cell-secreted factors, are needed. In addition, the field can learn from other disciplines, such as vascular and pulmonary medicine, which play a major role in many cardiovascular patients with advanced disease. This special cardiovascular issue illustrates the breadth of investigation currently under way for regeneration therapies for cardiovascular disease.
Winters et al. provide a direct comparison of multiple human cell and gene therapies using a small cardiac infarct model, which includes in vivo and in vitro analysis. This is one of the first studies directly comparing multiple biologics currently under investigation or planned for the near future.
The potential role of adipose-derived stem cells (ADSCs) in the treatment of cardiovascular disease has become increasingly clear. The ability to augment positive effects of ADSCs with sustained growth factor expression is demonstrated by Bagno et al. with insulin-like growth factor 1 (IGF-1) in a preclinical infarct model. Prochazka et al. report on the role of the secreted factors from ADSCs in treating critical limb ischemia, and Lu et al. provide evidence for the potential role of ADSCs in adult respiratory distress syndrome.
Zhang et al. provide evidence of benefit with the direct use of Apelin-13, one of the most potent stimulators of cardiac contractility in a rat infarct model.
A better understanding of the role of extracellular matrix is critical for the next generation of cardiac biological therapies. Gaetani et al. reported the impact of cardiac-derived extracellular matrix on the cardiogenic properties of human cardiac progenitor cells. Hatta et al. describe the benefit of uterine-derived stem cells for both vasculogenesis and myocardial healing in a preclinical model.
As we translate novel therapies into clinical trials, it is important to identify factors that may predict which patients may benefit from cell therapy. Taylor et al. from the NIH Cardiovascular Cell Therapy Research Network describe subpopulations of bone marrow mononuclear stem cells that led to improvement of left ventricular function in patients with heart failure with the FOCUS trial.
The design of cell therapy clinical trials for heart failure is central to the potential success of a trial. Henry et al. describe the rationale and trial design for the multicenter double-blind, placebo-controlled ixCELL-DCM trial for patients with ischemic heart failure, which recently reported a significant reduction in mortality and cardiovascular hospitalization in cell-treated patients compared to placebo.
Henry et al. also present the 2-year data for the phase 1 double-blind, placebo-controlled ACT-34 clinical trial, which demonstrated a significant improvement in exercise time and reduction in angina in CD34+-treated patients, with benefits maintained at 2 years.
Whereas both ixCell-DCM and ACT-34 used endocardial delivery of the cells directly into the myocardium, Tuma et al. present the 2-year data on the RESCUE-HF clinical trial, which delivered umbilical cord subepithelial cells via retrograde coronary sinus infusion in patients with heart failure, demonstrating safety in a multiple-dose escalation study.
Cardiac biologic therapy has advanced into phase 3 clinical trials. This special issue illustrates the wide range of cells, secreted factors, genes, and matrices under investigation. The continued understanding of how these components interact with each other will help lead the path to safer and more reproducible therapies for the future.
Footnotes
Acknowledgment
A.N.P. and T.D.H. were involved in the review of all manuscripts other than their own for this special issue. A.N.P. is a section editor of Cell Transplantation. Neither A.N.P. nor T.D.H. was involved in the review of manuscripts on which either was an author. Also, no member of the editorial board or editorial office affiliated with the authors' institutions was involved with the review process and/or decision making on the manuscripts.