Table 2.

Different properties of foetal, hiPSC-derived and adult cardiomyocytes.

Property	Foetal Cardiomyocytes	hiPSC-Derived Cardiomyocytes	Adult Cardiomyocytes	Impact on Cell Physiology	Ref.
Morphology	Round or polygonal-shaped with chaotic organisation	Mostly round, rod-shaped cells after >50 days in culture but remain smaller than adult cardiomyocytes with chaotic organisation.	Elongated and rod-shaped with an aspect ratio of 5:1; longitudinally aligned. Larger cell size and increased membrane capacitance	Elongated structure and organised longitudinal alignment facilitate fast electrical conduction and efficient muscle contraction	[131,132]
Nucleation	Mononucleated	Largely mononucleated, showing only sporadic nucleation	25–30% binucleated	Binucleation associated with reduced regenerative potential	[132,133]
Sarcomere	1.6 μm sarcomere spacing	Irregular, 10% of cell volume, 1.6–1.8 μm sarcomere spacing	Organised and aligned, 40% of cell volume, 2.2 μm sarcomere spacing	Increased volume, organisation and spacing associated with increased force generation	[134,135,136,137]
Titin	N2BA	N2BA	N2B	Adult isoforms enhance sarcomere elasticity	[138,139,140]
Myosin heavy chain	Predominantly β-isoform in ventricular cardiomyocytes, predominantly α-isoform in atrial cardiomyocytes	Equal expression of β- and α-isoforms, potentially due to mixed cardiomyocyte sub-type cultures	β-isoform almost exclusively expressed in ventricular cardiomyocytes, α-isoform almost exclusively expressed in atrial cardiomyocytes	Adult isotype shift enhances power generation, stiffness and signalling.	[141,142]
Myosin light chain	Predominant expression of MLC2v isotype in ventricular cardiomyocytes, and predominant expression of MLC2a isotype in atrial cardiomyocytes	Equal expression of both isotypes MLC2a and MLC2v, potentially due to mixed cardiomyocyte sub-type cultures	MLC2v isotype is almost exclusively expressed in ventricular cardiomyocytes, MLC2a isotype is almost exclusively expressed in atrial cardiomyocytes	Adult isotype shift enhances power generation, stiffness and signalling	[143,144,145,146]
Metabolism	Glycolysis	Glycolysis	Oxidative phosphorylation	Fatty acid oxidation increases oxygen use and increases ATP production	[147,148]
Mitochondria structure	Small and round, close to nucleus and at periphery	Slender and long, smaller than in adult cardiomyocytes, Close to nucleus and at the periphery	Oval shape, 30% total volume, In the direction of the sarcomere	Increased density and organisation of mitochondria change substrate utilisation from glucose and lactate to fatty acids	[149,150]
T-tubule system	Poorly developed and organised	Poorly developed and organised	Highly developed and organised	A highly organised and developed T-tubule system increases synchronous and efficient calcium activation through the cell	[136,145,151,152,153]
Gap junction	Circumferential on all sides of the membrane, rather than the end	Circumferential on all sides of the membrane, rather than the end	Polarised at ends (at intercalated discs)	Increased anisotropic force generation and conduction velocity in the longitudinal direction	[136,154,155,156]
Conduction velocity	?	25–43 cm/s	70–130 cm/s	Enhanced propagation of electrical signals	[157,158]
Calcium handling	Immature calcium handling and low expression of calcium handling proteins	Immature calcium handling and low expression of calcium handling proteins	Calcium-induced calcium release is mature and efficient, high expression of calcium handling proteins	Mature calcium handling leads to fast excitation-contraction coupling, increased calcium amplitude, increased force generation, faster activation and decay and synchronised contraction in multiple sarcomeres	[135,159]
Cell cycle	Mitogens drive proliferation	Mitogens drive proliferation	Mitogens drive hypertrophy	Reduced regenerative potential and increase in cardiomyocyte size	[130,156]
Sodium ion channel expression	Foetal isoform of INa	Foetal isoform of INa	Adult isoform of INa	Faster upstroke velocity from 50 V/s in foetal and hiPSC-derived cardiomyocytes to 250 V/s in adult cardiomyocytes	[160,161]
Potassium channel expression	Low expression of IK	Low expression of IK	High expression of IK	Reduced resting membrane potential from −60 mv in foetal and hiPSC-derived cardiomyocytes to −90 mv in adults	[156]
ECM binding	β1 integrin collagen I/fibronectin	β1 integrin collagen I/fibronectin	Laminin/basement membrane	Decreased proliferation	[157,162]

INa: sodium ion channel. IK: potassium ion channel. ECM: extracellular matrix.