Human stem cells for modeling heart disease and for drug discovery

Abstract

A major research focus in the field of cardiovascular medicine is the prospect of using stem cells and progenitor cells for cardiac regeneration. With the advent of induced pluripotent stem cell (iPSC) technology, major efforts are also underway to use iPSCs to model heart disease, to screen for new drugs, and to test candidate drugs for cardiotoxicity. Here, we discuss recent advances in the exciting fields of stem cells and cardiovascular disease.

Fig. 1. Adult and pluripotent stem cells for cardiovascular tissue repair

Shown are stem cell–based therapies for regenerative medicine that (A) are currently in clinical trials or (B and C) have potential as therapeutic strategies in the future. Adult stem cells and progenitors isolated from the bone marrow, adipose tissue, and blood can be transplanted into the heart without the need for expansion, whereas skeletal muscle and cardiac-derived stem cells require in vitro expansion before transplantation. Pluripotent stem cell and transdifferentiation strategies require both expansion and conversion to cardiomyocytes before transplantation, unless transdifferentiation takes place in vivo through delivery of transcription factors. ADSCs, adipose-derived stem cells; MSCs, mesenchymal stem cells; MNCs, mononuclear cells; S P, side population; CDCs, cardiosphere-derived cells; PBMCs, peripheral blood mononuclear cells; iPSCs, induced pluripotent stem cells; CMs, cardiomyocytes; CVPCs, cardiovascular progenitor cells; EPCs, endothelial progenitor cells.

Fig. 2. iPSC-derived cardiomyocytes for drug screening and toxicity testing

Because of the sensitivity of the hERG potassium ion channel to drug-induced cytotoxicity, the safety of new candidate drugs is tested by looking at their effects on hERG electrophysiology. This assay is routinely performed in Chinese hamster ovary cells or human embryonic kidney cells engineered to express hERG, which do not exhibit the complex physiology of human cardiomyocytes. Human cardiomyocytes derived from induced pluripotent stem cells (iPSCs) are promising new tools for drug discovery and have already permitted drug testing and toxicology studies for a variety of human cardiac disorders. These cardiac disorders, caused by a variety of mutations, include LQTS, CPVT, DCM, HCM, and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C).