Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

Abstract

Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived cardiomyocytes can be generated routinely with high yield and purity for disease research and drug development, and these cells are now gradually entering the clinical research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is the immature state of these cardiomyocytes. In this Review, we describe the structural and functional properties of cardiomyocytes and present the current approaches to mature PSC-derived cardiomyocytes. To date, the greatest success in maturation of PSC-derived cardiomyocytes has been with transplantation into the heart in animal models and the engineering of 3D heart tissues with electromechanical conditioning. In conventional 2D cell culture, biophysical stimuli such as mechanical loading, electrical stimulation and nanotopology cues all induce substantial maturation, particularly of the contractile cytoskeleton. Metabolism has emerged as a potent means to control maturation with unexpected effects on electrical and mechanical function. Different interventions induce distinct facets of maturation, suggesting that activating multiple signalling networks might lead to increased maturation. Despite considerable progress, we are still far from being able to generate PSC-derived cardiomyocytes with adult-like phenotypes in vitro. Future progress will come from identifying the developmental drivers of maturation and leveraging them to create more mature cardiomyocytes for research and regenerative medicine. In this Review, Murry and colleagues describe the hallmarks of cardiomyocyte maturation and the current approaches to mature stem cell-derived cardiomyocytes, highlighting challenges and future directions to generate cardiomyocytes with an optimal maturation state for use in research and regenerative medicine. Cardiomyocytes can be generated in vitro from stem cells with high throughput and purity at a clinically relevant scale, although their differentiation status resembles an embryonic state. Cardiomyocyte maturation entails adoption of multiple complex phenotypes, and a number of methods to mature stem cell-derived cardiomyocytes have been successful in driving the cells towards a postnatal state. Stem cell-derived cardiomyocyte phenotypes have been characterized with the use of global systems approaches, which has uncovered novel regulators and insights for maturation. Moving forward, strategies for cardiomyocyte maturation will require indication-specific optimization for intended applications of stem cell-derived cardiomyocytes, leveraging an optimal maturation state while utilizing combinatorial approaches.