Heart diseases are a major cause of death worldwide. Loss of cardiomyocytes (CMs) due to aging or disease is irreversible. Current therapeutic regimes are palliative, and in end-stage heart failure, transplantation remains the last resort but is significantly hampered by a severe shortage of donors. Cell replacement therapy represents one possible alternative, but significant hurdles must be overcome.
Self-renewing pluripotent human embryonic stem cells (hESCs) can differentiate into all cell types, including CMs. Direct reprogramming of adult somatic cells to induced pluripotent stem cells (iPSCs) has advanced the field of personalize medicine. The availability of hESC/iPSCs have enabled researchers to gain novel biological insights and to pursue heart regeneration. Despite these promises, substantial hurdles remain for translating pluripotent stem cells (PSCs) into cell-based therapies and for improved disease modeling, cardiotoxicity testing and drug screening.
In a series of studies, we have shown that hESC-CMs have 1) immature Ca2+-handling, with an attenuated transient and heart failure-like U-shaped Ca2+ propagation wavefronts due to the lack of t-tubules; 2) immature electrical properties; 3) a small physical size (~10-fold less than adult CMs); 4) an absence of ordered organization at the sub-, single- and multi-cellular levels; 5) high cell heterogeneity, even from directed cardiac differentiation, consisting of a mixture of pacemaker, atrial and ventricular derivatives; 6) sub-lineage specification is poorly understood; 7) no convenient cardiac/chamber-specific surface marker for robust purification; 8) poor graft survival; 9) poor understanding of immunobiology; and 10) an uncertain durability in terms of safety and efficacy.