Human embryonic stem cells and cardiac repair

Abstract

The muscle lost after a myocardial infarction is replaced with noncontractile scar tissue, often initiating heart failure. Whole-organ cardiac transplantation is the only currently available clinical means of replacing the lost muscle, but this option is limited by the inadequate supply of donor hearts. Thus, cell-based cardiac repair has attracted considerable interest as an alternative means of ameliorating cardiac injury. Because of their tremendous capacity for expansion and unquestioned cardiac potential, pluripotent human embryonic stem cells (hESCs) represent an attractive candidate cell source for obtaining cardiomyocytes and other useful mesenchymal cell types for such therapies. Human embryonic stem cell-derived cardiomyocytes exhibit a committed cardiac phenotype and robust proliferative capacity, and recent testing in rodent infarct models indicates that they can partially remuscularize injured hearts and improve contractile function. Although the latter successes give good reason for optimism, considerable challenges remain in the successful application of hESCs to cardiac repair, including the need for preparations of high cardiac purity, improved methods of delivery, and approaches to overcome immune rejection and other causes of graft cell death. This review will describe the phenotype of hESC-derived cardiomyocytes and preclinical experience with these cells and will consider strategies to overcoming the aforementioned challenges.

Figure 1. Human embryonic stem cell derived cardiomyocytes (hESC-CMs) exhibit an unambiguous cardiac phenotype

A-B. hESC-CMs express expected cardiac-specific markers, as demonstrated by immunocytochemical analysis. A: cardiac troponin I (green) and Nkx2.5 (red). B: sarcomeric myosin heavy chain (green) and N-cadherin (red). Nuclei were stained with DAPI (blue). Bar=50 μm. C. hESC-CMs exhibit expected electrophysiologic properties and, as illustrated by these representative current-clamp recordings, include cardiomyocytes with distinct ventricular-, nodal-, and atrial-like action potential properties. D. In response to depolarization (in this case, by field stimulation at 1Hz), hESC-CMs exhibit [Ca²⁺]_i transients that can be detected with the fluorescent calcium rhod-4 AM. (from unpublished data by Zhu, Santana, and Laflamme)