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Table 2 Effects of external factors on maturation

From: Physical developmental cues for the maturation of human pluripotent stem cell-derived cardiomyocytes

External factors Effects on developmental maturation Reference
Substrate stiffness/ Affects differentiation efficiencies. Intermediate-stiffness hydrogels lead to the highest efficiencies Hazeltine et al. 2014 [97]
Two/three-dimensional culture Increases organization of sarcomeric myofilaments Ou et al. 2011 [63]
Zhang et al. 2013 [12]
Increases cardiac gene expression Pal et al. 2013 [64]
Turnbull et al. 2014 [13]
Increases contractile and Ca2+ handling protein expression Tulloch et al. 2011 [10]
Zhang et al. 2013 [12]
Promotes alignment and anisotropy Liau et al. 2011 [66]
Promotes functional maturation in general Christoforou et al. 2013 [67]
  Two-dimensional alignment and groove widths between 30 and 80 μm promote alignment and improve sarcomere structures Salick et al. 2014 [92]
Mechanical stimulation Increases expression of cardiac α-actin and MYH6, and enhances expression of cardiac transcription factors Gwak et al. 2008 [98]
Improves tissue morphology and enhances active force levels Kensah et al. 2013 [99]
Increases cell alignment Tulloch et al. 2011 [10]
Schaaf et al. 2011 [11]
Thavandiran et al. 2013 [101]
Zhang et al. 2013 [12]
Increases proliferation rates Tulloch et al. 2011 [10]
Increases AP duration and upstroke velocity, but leads to a less negative MDP Schaaf et al. 2011 [11]
Increases cell size, cytoskeletal assembly and sarcomeric organization Foldes et al. 2011 [116]
  Cyclic stretch improves TNNT2 and Cx43 expression, increases contraction rates and shortens calcium transients Mihic et al. 2014 [100]
Electrical stimulation Leads to better structured and organized myofilaments Lieu et al. 2013 [15]
  Produces cell elongation, affects expression of a group of cardiac-related genes Chan et al. 2013 [102]
Chen et al. 2009 [104]
  Improves cardiomyocyte alignment, cross-striation patterns and force development Hirt et al. 2014 [103]
Energy substrate Elicits ARVD/C phenotype of increased apoptosis, elevated lipogenesis, and impaired calcium handling in PKP2 mutants Kim et al. 2013 [83]
  Galactose and fatty acids increase oxidative phosphorylation levels, reserve capacity, and maximum respiratory capacity in mitochondria Rana et al. 2012 [120]
  Glucose depletion along with lactose supplementation increase cardiomyocyte purity Tohyama et al. 2013 [121]
  Induction of mitochondrial biogenesis increases cardiomyocyte differentiation Prowse et al. 2012 [126]
Other Stimulating p38-MAPK increases cell size, improves sarcomere and cytoskeletal assembly Foldes et al. 2011 [116]
Heineke and Molkentin 2006 [117]
Thyroid hormone increases cardiomyocyte size, sarcomere length, contractile force and anisotropy Yang et al. 2014 [18]
Adrenergic agonists produce hypertrophy Foldes et al. 2011 [116]
  IGF1 together with electrical or electromechanical stimulation improve NRVM engineered tissue function, SERCA2a and TNNT2 expression Park et al. 2014 [119]
   Morgan and Black 2014 [118]
  1. AP, action potential; ARVD/C, arrhythmogenic right ventricular dysplasia/cardiomyopathy; Cx43, connexin 43; IGF-1, insulin-like growth factor 1; MAPK, mitogen-activated protein kinase; MDP, maximal diastolic potential; NRVM, neonatal rat ventricular myocyte; TNNT2, cardiac troponin T.