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.
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.
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We thank the members of the Murry Laboratory for productive discussions on the biology of cardiac maturation. We also thank our peer-reviewers, who made this manuscript better. The authors’ work is supported in part by NIH grants R01HL128362, U54DK107979, R01HL141570, R01HL146868 and R01HL128368, an award from the Fondation Leducq Transatlantic Network of Excellence and a grant from the Robert B. McMillen Foundation. N.M. is supported by a fellowship from the Japan Society for the Promotion of Science.
C.E.M. is a scientific founder and equity holder in Sana Biotechnology. The other authors declare no competing interests.
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- Pluripotent stem cells
Stem cells with the capacity to differentiate into any cell type of the embryo. This term encompasses embryonic stem cells and induced pluripotent stem cells.
- Embryonic stages
In humans, the first trimester of in utero development.
- Fetal stages
In humans, the second and third trimesters of in utero development.
- Immature cardiomyocytes
Underdeveloped cardiomyocytes that lack the characteristics of adult cardiomyocytes.
The state in which cells or organisms have more than two complete sets of chromosomes.
- Membrane capacitance
Ratio of electric charge to membrane potential that is directly proportional to the cell surface area.
- Mature cardiomyocytes
Cardiomyocytes that are fully developed and resemble in vivo adult cells in structure and function.
The capacity to stretch or otherwise deform in response to a change in tension, mathematically defined as the change in length (strain) divided by the change in force (stress).
Force transmitted axially during contraction or relaxation.
(miRNAs). Small non-coding RNAs (~20 nucleotides) that downregulate protein levels through post-transcriptional regulation of mRNA.
- Human induced pluripotent stem cell
(hiPSC). Stem cell generated by reprogramming a terminally differentiated, somatic cell to a pluripotent state.
Genetically distinct but from the same species.
- Elastic modulus
The stiffness of a material, mathematically defined as the change in stress divided by the change in strain (that is, the reciprocal of compliant).
A commercially available extracellular matrix secreted by mouse sarcoma cells.
The principal fibrillar extracellular matrix protein in the heart.
A blood protein that self-assembles into a nanofiber meshwork; its natural function is in blood coagulation, but it has been repurposed for tissue engineering scaffolds.
- Isometric contractile force
A contraction in which tension increases without changes in muscle length.
- Frank–Starling relationship
The property of heart muscle whereby an increase in resting tension (preload) linearly increases the strength of contraction.
- Force–frequency relationship
The property of mature heart muscle in which increasing frequency of stimulation results in greater force generation.
Tension on cardiomyocytes experienced during systole, typically provided by blood pressure.
- Auxotonic contraction
A form of contraction in which the muscle shortens against a changing tension.
Structure in the cardiomyocyte located at the sarcomere Z line, formed by a T-tubule paired with a terminal cisterna of the sarcoplasmic reticulum.
- Conduction velocity
The speed of propagation of an action potential across a cell or multicellular tissue.
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Karbassi, E., Fenix, A., Marchiano, S. et al. Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine. Nat Rev Cardiol 17, 341–359 (2020). https://doi.org/10.1038/s41569-019-0331-x
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