Translational aspects of cardiac cell therapy

Abstract

Cell therapy has been intensely studied for over a decade as a potential treatment for ischaemic heart disease. While initial trials using skeletal myoblasts, bone marrow cells and peripheral blood stem cells showed promise in improving cardiac function, benefits were found to be short-lived likely related to limited survival and engraftment of the delivered cells. The discovery of putative cardiac 'progenitor' cells as well as the creation of induced pluripotent stem cells has led to the delivery of cells potentially capable of electromechanical integration into existing tissue. An alternative strategy involving either direct reprogramming of endogenous cardiac fibroblasts or stimulation of resident cardiomyocytes to regenerate new myocytes can potentially overcome the limitations of exogenous cell delivery. Complimentary approaches utilizing combination cell therapy and bioengineering techniques may be necessary to provide the proper milieu for clinically significant regeneration. Clinical trials employing bone marrow cells, mesenchymal stem cells and cardiac progenitor cells have demonstrated safety of catheter based cell delivery, with suggestion of limited improvement in ventricular function and reduction in infarct size. Ongoing trials are investigating potential benefits to outcome such as morbidity and mortality. These and future trials will clarify the optimal cell types and delivery conditions for therapeutic effect.

Keywords: biomaterials; cardiac progenitor cell; cardiac regeneration; cell therapy; combination cell therapy; direct reprogramming.

Figure 1

Cell and tissue sources of cells for exogenous cell delivery. Multiple clinical trials have investigated non-cardiac cells including (A) skeletal myoblasts, (B) adipose-derived stem cells, and (D) bone marrow-derived stem cells, with limited evidence of cell engraftment or clinical efficacy. Clinical trials utilizing cells obtained from biopsied cardiac tissue (C) including cardiac ‘progenitor’ cells and cardiosphere-derived cells have provided the strongest evidence to date for clinical efficacy of exogenous cell therapy. Embryonic stem cells (E) and induced pluripotent stem cells (F) can be used as a source of cardiomyocytes potentially capable of electromechanical integration into native cardiac tissue.

Figure 2

A combined approach for amelioration of injury and rejuvenation of cardiac tissue. Successful cardiac regeneration will likely necessitate a combination of therapeutic approaches. (A) Delivery of exogenous cells has been demonstrated via epicardial, intramyocardial (endocardial), intracoronary and intravenous routes. (B) Fibroblasts directly reprogrammed into cardiomyocytes either in vitro or in vivo can potentially serve as an abundant source of cells for cardiac regeneration. (C) Stimulation of native cardiomyocyte proliferation may be possible using a number of protein- and nucleic acid- based factors. Delivery of multiple cell types (E) along with delivery of biomaterials-based scaffolding (D) may be necessary for optimal cell engraftment and tissue regeneration.