Highlighting the Field of Cardiovascular Regenerative Medicine
Authors: Wolfram-Hubertus Zimmermann, Seppo Yla-Herttuala, Roger J. Hajjar
Journal: Molecular Therapy (2018)

The incidence of ischemic heart disease continues to increase in the world. Myocardial infarction, the subsequent sequelae of ventricular dilation, and heart failure are consequences of acute or chronic losses of myocardial cells. The fibrotic replacements of these lost cardiac cells lead to further myocardial dysfunction and systemic congestion. Despite advances in medical and device-based therapies, there remains a clear unmet need for effective treatments for this disease state. In this special issue of Molecular Therapy, we review this exciting field of cardiac regenerative medicine with invited reviews and original research articles from leading laboratories that, together, convey the state of the art. Novel approaches have been used to repair the damaged heart and chief among them is cardiac regeneration. Over the last two decades, a number of approaches have been studied to stimulate heart regeneration. Initially, the efforts were focused on transplanting non-cardiac cells into compromised hearts. These included skeletal myoblasts, bone marrow cells, and mesenchymal stem cells. Dr. Josh Hare reviews the results of various clinical trials using mesenchymal stem cells (MSCs) in ischemic and non-ischemic cardiomyopathy, focusing on the route of delivery, cell populations, doses, and timing for treatment. Even though the results from these trials showed some cardiac improvement with a reduction in scar size, the effects were small. Subsequently, cardiac progenitor cells (CPCs) were delivered to failing ischemic hearts. Many CPCs were used pre-clinically, such as islet-1 cells (as employed by Dr. Ken Chien in an original research report in this issue) and ckit+ cells. Clinically, ckit+ cells have been delivered either as pure cells or as part of cardiospheres with variable, if minimal, beneficial effects. The availability of human embryonic stem cells (ESCs) followed by induced pluripotent stem cells (iPSCs) and the advent of protocols for their directed differentiatiom formed the basis of a new generation of cardiomyocytes. Dr. Joe Wu’s review recapitulates the various ongoing and completed pre-clinical and clinical trials using ESC- and iPSC-derived cardiomyocytes. Even though there is significant promise in differentiating cardiac myocytes from pluripotent stem cells, the real power of this methodology is its combination with engineered tissues, which can more effectively integrate into the targeted organs (see original research by Flugelman et al. in this issue). Angiogenesis augments the stability and sustainability of cardiac regeneration, and this issue includes two original research reports in this area from the labs of Seppo Yla-Herttuala and Andy Baker. Cell-free methods of cardiac repair have gained much interest recently. Extracellular vesicles such as exosomes, carrying a variety of microRNAs, long noncoding RNAs, and other factors have been shown to have therapeutic effects in cardiac regeneration. The field of exosome biology is reviewed by Dr. Susmita Sahoo, who highlights the various potentials of exosomes. Paracrine factors have also been implicated in cardiac repair. These factors excreted by MSCs, CPCs, ESCs, or iPSC-derived cardiomyoctes have all been shown to have beneficial effects. However, none of these factors or cells have been found to induce robust cardiogenesis. Our knowledge of cardiac proliferation has increased significantly by the specific definition of the neonatal time period during which cardiac myocytes can divide. In addition, there is now proof that there exists a low level of cardiac proliferation throughout adulthood. Our fourth and final invited review by Vincent Christoffels and colleagues summarizes these data. With the unraveling of signaling pathways underlying cardiac division in the early neonatal heart and evolving technology to genetically manipulate these pathways, it may become possible to translate the findings of induced cardiac cell division from pre-clinical models to the clinic. The editors of this Special Issue are immensely grateful to the authors of the invited reviews that provide an excellent outline of the state of this field as well as to those research teams that responded to the call for papers, resulting in many of the original research articles that comprise this collection of exciting research results.