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Longitudinal metabolic profiling of cardiomyocytes derived from human-induced pluripotent stem cells

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Abstract

Human-induced pluripotent stem cells (h-iPSCs) are a unique in vitro model for cardiovascular research. To realize the potential applications of h-iPSCs-derived cardiomyocytes (CMs) for drug testing or regenerative medicine and disease modeling, characterization of the metabolic features is critical. Here, we show the transcriptional profile during stages of cardiomyogenesis of h-iPSCs-derived CMs. CM differentiation was not only characterized by the expression of mature structural components (MLC2v, MYH7) but also accompanied by a significant increase in mature metabolic gene expression and activity. Our data revealed a distinct substrate switch from glucose to fatty acids utilization for ATP production. Basal respiration and respiratory capacity in 9 days h-iPSCs-derived CMs were glycolysis-dependent with a shift towards a more oxidative metabolic phenotype at 14 and 28 day old CMs. Furthermore, mitochondrial analysis characterized the early and mature forms of mitochondria during cardiomyogenesis. These results suggest that changes in cellular metabolic phenotype are accompanied by increased O2 consumption and ATP synthesis to fulfill the metabolic needs of mature CMs activity. To further determine functionality, the physiological response of h-iPSCs-derived CMs to β-adrenergic stimulation was tested. These data provide a unique in vitro human heart model for the understanding of CM physiology and metabolic function which may provide useful insight into metabolic diseases as well as novel therapeutic options.

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Abbreviations

β-AR:

β-Adrenergic receptor

CD36:

Cluster of differentiation 36

CM:

Cardiomyocyte

CPT-1B:

Carnitine-palmitoyl-CoA transferase-1B

DGAT1:

Diglyceride acyltransferase 1

DRP1:

Dynamin-related protein 1

ESC:

Embryonic stem cells

FA:

Fatty acid

FAO:

Fatty acid oxidation

FCM:

Flow cytometry

GLUT:

Glucose transporters

h-ESCs:

Human-embryonic stem cells

h-iPSCs:

Human-induced pluripotent stem cells

MFF:

Mitochondrial fission factor

MFN2:

Mitofusin-2

MLC2a:

Myosin light chain 2 isoform atrial

MLC2v:

Myosin light chain 2 isoform ventricular

OPA1:

Optic atrophy 1

PDK4:

Pyruvate dehydrogenase kinase 4

PFA:

Paraformaldehyde

PGC-1α:

PPARγ coactivator-1α

PP2A:

Protein phosphatase 2A

PPARα:

Peroxisome proliferator-activated receptor-α

ROS Reactive:

Reactive oxygen species

SM:

Standard manufacturer’s maintenance medium

TEM:

Transmission electron microscopy

References

  1. Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacin M, Vidal H, Rivera F, Brand M, Zorzano A (2003) Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem 278:17190–17197. https://doi.org/10.1074/jbc.M212754200

    Article  PubMed  Google Scholar 

  2. Batten BE, Albertini DF, Ducibella T (1987) Patterns of organelle distribution in mouse embryos during preimplantation development. Am J Anat 178:204–213. https://doi.org/10.1002/aja.1001780212

    Article  CAS  PubMed  Google Scholar 

  3. Bekhite MM, Finkensieper A, Binas S, Muller J, Wetzker R, Figulla HR, Sauer H, Wartenberg M (2011) VEGF-mediated PI3K class IA and PKC signaling in cardiomyogenesis and vasculogenesis of mouse embryonic stem cells. J Cell Sci 124:1819–1830. https://doi.org/10.1242/jcs.077594

    Article  CAS  PubMed  Google Scholar 

  4. Bekhite MM, Muller V, Troger SH, Muller JP, Figulla HR, Sauer H, Wartenberg M (2016) Involvement of phosphoinositide 3-kinase class IA (PI3K 110alpha) and NADPH oxidase 1 (NOX1) in regulation of vascular differentiation induced by vascular endothelial growth factor (VEGF) in mouse embryonic stem cells. Cell Tissue Res 364:159–174. https://doi.org/10.1007/s00441-015-2303-8

    Article  CAS  PubMed  Google Scholar 

  5. Bezenah JR, Kong YP, Putnam AJ (2018) Evaluating the potential of endothelial cells derived from human induced pluripotent stem cells to form microvascular networks in 3D cultures. Sci Rep 8:2671. https://doi.org/10.1038/s41598-018-20966-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bolton TB (2006) Calcium events in smooth muscles and their interstitial cells; physiological roles of sparks. J Physiol 570:5–11. https://doi.org/10.1113/jphysiol.2005.095604

    Article  CAS  PubMed  Google Scholar 

  7. Cao YP, Zheng M (2019) Mitochondrial dynamics and inter-mitochondrial communication in the heart. Arch Biochem Biophys 663:214–219. https://doi.org/10.1016/j.abb.2019.01.017

    Article  CAS  PubMed  Google Scholar 

  8. Chaudhry FA, Tauke JT, Alessandrini RS, Vardi G, Parker MA, Bonow RO (1999) Prognostic implications of myocardial contractile reserve in patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 34:730–738. https://doi.org/10.1016/s0735-1097(99)00252-1

    Article  CAS  PubMed  Google Scholar 

  9. Correia C, Koshkin A, Duarte P, Hu D, Teixeira A, Domian I, Serra M, Alves PM (2017) Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Sci Rep 7:8590. https://doi.org/10.1038/s41598-017-08713-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Elliott DA, Braam SR, Koutsis K, Ng ES, Jenny R, Lagerqvist EL, Biben C, Hatzistavrou T, Hirst CE, Yu QC, Skelton RJ, Ward-van Oostwaard D, Lim SM, Khammy O, Li X, Hawes SM, Davis RP, Goulburn AL, Passier R, Prall OW, Haynes JM, Pouton CW, Kaye DM, Mummery CL, Elefanty AG, Stanley EG (2011) NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat Methods 8:1037–1040. https://doi.org/10.1038/nmeth.1740

    Article  CAS  PubMed  Google Scholar 

  11. Facucho-Oliveira JM, Alderson J, Spikings EC, Egginton S, St John JC (2007) Mitochondrial DNA replication during differentiation of murine embryonic stem cells. J Cell Sci 120:4025–4034. https://doi.org/10.1242/jcs.016972

    Article  CAS  PubMed  Google Scholar 

  12. Fermini B, Fossa AA (2003) The impact of drug-induced QT interval prolongation on drug discovery and development. Nat Rev Drug Discovery 2:439–447. https://doi.org/10.1038/nrd1108

    Article  CAS  PubMed  Google Scholar 

  13. Ginsburg KS, Bers DM (2004) Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and Ca2+ current trigger. J Physiol 556:463–480. https://doi.org/10.1113/jphysiol.2003.055384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goldberg IJ, Trent CM, Schulze PC (2012) Lipid metabolism and toxicity in the heart. Cell Metab 15:805–812. https://doi.org/10.1016/j.cmet.2012.04.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Guatimosim S, Dilly K, Santana LF, Saleet Jafri M, Sobie EA, Lederer WJ (2002) Local Ca(2+) signaling and EC coupling in heart: Ca(2+) sparks and the regulation of the [Ca(2+)](i) transient. J Mol Cell Cardiol 34:941–950. https://doi.org/10.1006/jmcc.2002.2032

    Article  CAS  PubMed  Google Scholar 

  16. Haege S, Einer C, Thiele S, Mueller W, Nietzsche S, Lupp A, Mackay F, Schulz S, Stumm R (2012) CXC chemokine receptor 7 (CXCR7) regulates CXCR4 protein expression and capillary tuft development in mouse kidney. PLoS ONE 7:e42814. https://doi.org/10.1371/journal.pone.0042814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. He JQ, Ma Y, Lee Y, Thomson JA, Kamp TJ (2003) Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ Res 93:32–39. https://doi.org/10.1161/01.RES.0000080317.92718.99

    Article  CAS  PubMed  Google Scholar 

  18. Hu D, Linders A, Yamak A, Correia C, Kijlstra JD, Garakani A, Xiao L, Milan DJ, van der Meer P, Serra M, Alves PM, Domian IJ (2018) Metabolic maturation of human pluripotent stem cell-derived cardiomyocytes by inhibition of HIF1alpha and LDHA. Circ Res 123:1066–1079. https://doi.org/10.1161/CIRCRESAHA.118.313249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jang A, Xiong Q, Zhang P, Zhang J (2016) Transmurally differentiated measurement of ATP hydrolysis rates in the in vivo porcine hearts. Magn Reson Med 75:1859–1866. https://doi.org/10.1002/mrm.26162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ji H, Kim HS, Kim HW, Leong KW (2017) Application of induced pluripotent stem cells to model smooth muscle cell function in vascular diseases. Curr Opin Biomed Eng 1:38–44. https://doi.org/10.1016/j.cobme.2017.02.005

    Article  PubMed  PubMed Central  Google Scholar 

  21. Karakikes I, Ameen M, Termglinchan V, Wu JC (2015) Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. Circ Res 117:80–88. https://doi.org/10.1161/CIRCRESAHA.117.305365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kitajima S, Takagi A, Inoue T, Saga Y (2000) MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development 127:3215–3226

    CAS  PubMed  Google Scholar 

  23. Kolwicz SC Jr, Tian R (2011) Glucose metabolism and cardiac hypertrophy. Cardiovasc Res 90:194–201. https://doi.org/10.1093/cvr/cvr071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kosloski LM, Bales IK, Allen KB, Walker BL, Borkon AM, Stuart RS, Pak AF, Wacker MJ (2009) Purification of cardiac myocytes from human heart biopsies for gene expression analysis. Am J Physiol Heart Circ Physiol 297:H1163–1169. https://doi.org/10.1152/ajpheart.00118.2009

    Article  CAS  PubMed  Google Scholar 

  25. Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C, Leiden JM (1997) GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11:1048–1060. https://doi.org/10.1101/gad.11.8.1048

    Article  CAS  PubMed  Google Scholar 

  26. Larsen TS, Aasum E (2008) Metabolic (in)flexibility of the diabetic heart. Cardiovasc Drugs Ther 22:91–95. https://doi.org/10.1007/s10557-008-6083-1

    Article  CAS  PubMed  Google Scholar 

  27. Laverty H, Benson C, Cartwright E, Cross M, Garland C, Hammond T, Holloway C, McMahon N, Milligan J, Park B, Pirmohamed M, Pollard C, Radford J, Roome N, Sager P, Singh S, Suter T, Suter W, Trafford A, Volders P, Wallis R, Weaver R, York M, Valentin J (2011) How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines? Br J Pharmacol 163:675–693. https://doi.org/10.1111/j.1476-5381.2011.01255.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856. https://doi.org/10.1172/JCI10268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, Raval KK, Zhang J, Kamp TJ, Palecek SP (2012) Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci USA 109:E1848–1857. https://doi.org/10.1073/pnas.1200250109

    Article  PubMed  Google Scholar 

  30. Lian X, Zhang J, Azarin SM, Zhu K, Hazeltine LB, Bao X, Hsiao C, Kamp TJ, Palecek SP (2013) Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions. Nat Protoc 8:162–175. https://doi.org/10.1038/nprot.2012.150

    Article  CAS  PubMed  Google Scholar 

  31. Liang P, Lan F, Lee AS, Gong T, Sanchez-Freire V, Wang Y, Diecke S, Sallam K, Knowles JW, Wang PJ, Nguyen PK, Bers DM, Robbins RC, Wu JC (2013) Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation 127:1677–1691. https://doi.org/10.1161/CIRCULATIONAHA.113.001883

    Article  CAS  PubMed  Google Scholar 

  32. Lopaschuk GD, Jaswal JS (2010) Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J Cardiovasc Pharmacol 56:130–140. https://doi.org/10.1097/FJC.0b013e3181e74a14

    Article  CAS  PubMed  Google Scholar 

  33. Mazrouei S, Sharifpanah F, Bekhite MM, Figulla H-R, Sauer H, Wartenberg M (2015) Cardiomyogenesis of embryonic stem cells upon purinergic receptor activation by ADP and ATP. Purinergic Signal 11:491–506. https://doi.org/10.1007/s11302-015-9468-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mummery CL, Zhang J, Ng ES, Elliott DA, Elefanty AG, Kamp TJ (2012) Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. Circ Res 111:344–358. https://doi.org/10.1161/CIRCRESAHA.110.227512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Neely JR, Morgan HE (1974) Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 36:413–459. https://doi.org/10.1146/annurev.ph.36.030174.002213

    Article  CAS  PubMed  Google Scholar 

  36. Nose N, Werner RA, Ueda Y, Gunther K, Lapa C, Javadi MS, Fukushima K, Edenhofer F, Higuchi T (2018) Metabolic substrate shift in human induced pluripotent stem cells during cardiac differentiation: functional assessment using in vitro radionuclide uptake assay. Int J Cardiol 269:229–234. https://doi.org/10.1016/j.ijcard.2018.06.089

    Article  PubMed  Google Scholar 

  37. Osellame LD, Singh AP, Stroud DA, Palmer CS, Stojanovski D, Ramachandran R, Ryan MT (2016) Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission. J Cell Sci 129:2170–2181. https://doi.org/10.1242/jcs.185165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Piquereau J, Ventura-Clapier R (2018) Maturation of cardiac energy metabolism during perinatal development. Front Physiol 9:959. https://doi.org/10.3389/fphys.2018.00959

    Article  PubMed  PubMed Central  Google Scholar 

  39. Prigione A, Adjaye J (2010) Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells. Int J Dev Biol 54:1729–1741. https://doi.org/10.1387/ijdb.103198ap

    Article  PubMed  Google Scholar 

  40. Ramachandra CJA, Mehta A, Wong P, Ja K, Fritsche-Danielson R, Bhat RV, Hausenloy DJ, Kovalik JP, Shim W (2018) Fatty acid metabolism driven mitochondrial bioenergetics promotes advanced developmental phenotypes in human induced pluripotent stem cell derived cardiomyocytes. Int J Cardiol 272:288–297. https://doi.org/10.1016/j.ijcard.2018.08.069

    Article  PubMed  Google Scholar 

  41. Reiser PJ, Portman MA, Ning XH, Schomisch Moravec C (2001) Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am J Physiol Heart Circ Physiol 280:H1814–1820. https://doi.org/10.1152/ajpheart.2001.280.4.H1814

    Article  CAS  PubMed  Google Scholar 

  42. Segev H, Kenyagin-Karsenti D, Fishman B, Gerecht-Nir S, Ziskind A, Amit M, Coleman R, Itskovitz-Eldor J (2005) Molecular analysis of cardiomyocytes derived from human embryonic stem cells. Dev Growth Differ 47:295–306. https://doi.org/10.1111/j.1440-169X.2005.00803.x

    Article  CAS  PubMed  Google Scholar 

  43. Sesaki H, Jensen RE (1999) Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J Cell Biol 147:699–706. https://doi.org/10.1083/jcb.147.4.699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sharifpanah F, Saliu F, Bekhite MM, Wartenberg M, Sauer H (2014) β-adrenergic receptor antagonists inhibit vasculogenesis of embryonic stem cells by downregulation of nitric oxide generation and interference with VEGF signalling. Cell Tissue Res 358:443–452. https://doi.org/10.1007/s00441-014-1976-8

    Article  CAS  PubMed  Google Scholar 

  45. Sharma A, Li G, Rajarajan K, Hamaguchi R, Burridge PW, Wu SM (2015) Derivation of highly purified cardiomyocytes from human induced pluripotent stem cells using small molecule-modulated differentiation and subsequent glucose starvation. J Vis Exp. https://doi.org/10.3791/52628

    Article  PubMed  PubMed Central  Google Scholar 

  46. Skulachev VP (2001) Mitochondrial filaments and clusters as intracellular power-transmitting cables. Trends Biochem Sci 26:23–29

    Article  CAS  Google Scholar 

  47. Song H, Chung SK, Xu Y (2010) Modeling disease in human ESCs using an efficient BAC-based homologous recombination system. Cell Stem Cell 6:80–89. https://doi.org/10.1016/j.stem.2009.11.016

    Article  CAS  PubMed  Google Scholar 

  48. Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85:1093–1129. https://doi.org/10.1152/physrev.00006.2004

    Article  CAS  Google Scholar 

  49. Taegtmeyer H, Sen S, Vela D (2010) Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann N Y Acad Sci 1188:191–198. https://doi.org/10.1111/j.1749-6632.2009.05100.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. https://doi.org/10.1016/j.cell.2007.11.019

    Article  CAS  PubMed  Google Scholar 

  51. Tohyama S, Hattori F, Sano M, Hishiki T, Nagahata Y, Matsuura T, Hashimoto H, Suzuki T, Yamashita H, Satoh Y, Egashira T, Seki T, Muraoka N, Yamakawa H, Ohgino Y, Tanaka T, Yoichi M, Yuasa S, Murata M, Suematsu M, Fukuda K (2013) Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 12:127–137. https://doi.org/10.1016/j.stem.2012.09.013

    Article  CAS  PubMed  Google Scholar 

  52. Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da Cruz S, Clerc P, Raschke I, Merkwirth C, Ehses S, Krause F, Chan DC, Alexander C, Bauer C, Youle R, Langer T, Martinou JC (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28:1589–1600. https://doi.org/10.1038/emboj.2009.89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ulmer BM, Stoehr A, Schulze ML, Patel S, Gucek M, Mannhardt I, Funcke S, Murphy E, Eschenhagen T, Hansen A (2018) Contractile work contributes to maturation of energy metabolism in hiPSC-derived cardiomyocytes. Stem Cell Rep 10:834–847. https://doi.org/10.1016/j.stemcr.2018.01.039

    Article  CAS  Google Scholar 

  54. Wang G, McCain ML, Yang L, He A, Pasqualini FS, Agarwal A, Yuan H, Jiang D, Zhang D, Zangi L, Geva J, Roberts AE, Ma Q, Ding J, Chen J, Wang DZ, Li K, Wang J, Wanders RJ, Kulik W, Vaz FM, Laflamme MA, Murry CE, Chien KR, Kelley RI, Church GM, Parker KK, Pu WT (2014) Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med 20:616–623. https://doi.org/10.1038/nm.3545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884. https://doi.org/10.1038/nrm3013

    Article  CAS  Google Scholar 

  56. Wilding M, Dale B, Marino M, di Matteo L, Alviggi C, Pisaturo ML, Lombardi L, De Placido G (2001) Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos. Hum Reprod 16:909–917. https://doi.org/10.1093/humrep/16.5.909

    Article  CAS  PubMed  Google Scholar 

  57. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124. https://doi.org/10.1016/S0092-8674(00)80611-X

    Article  CAS  PubMed  Google Scholar 

  58. Xiong Q, Ye L, Zhang P, Lepley M, Tian J, Li J, Zhang L, Swingen C, Vaughan JT, Kaufman DS, Zhang J (2013) Functional consequences of human induced pluripotent stem cell therapy: myocardial ATP turnover rate in the in vivo swine heart with postinfarction remodeling. Circulation 127:997–1008. https://doi.org/10.1161/CIRCULATIONAHA.112.000641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ye L, Chang YH, Xiong Q, Zhang P, Zhang L, Somasundaram P, Lepley M, Swingen C, Su L, Wendel JS, Guo J, Jang A, Rosenbush D, Greder L, Dutton JR, Zhang J, Kamp TJ, Kaufman DS, Ge Y, Zhang J (2014) Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Cell Stem Cell 15:750–761. https://doi.org/10.1016/j.stem.2014.11.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ye L, Zimmermann WH, Garry DJ, Zhang J (2013) Patching the heart: cardiac repair from within and outside. Circ Res 113:922–932. https://doi.org/10.1161/CIRCRESAHA.113.300216

    Article  CAS  PubMed  Google Scholar 

  61. Zhang M, D'Aniello C, Verkerk AO, Wrobel E, Frank S, Ward-van Oostwaard D, Piccini I, Freund C, Rao J, Seebohm G, Atsma DE, Schulze-Bahr E, Mummery CL, Greber B, Bellin M (2014) Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue. Proc Natl Acad Sci USA 111:E5383–5392. https://doi.org/10.1073/pnas.1419553111

    Article  CAS  PubMed  Google Scholar 

  62. Zhang M, Schulte JS, Heinick A, Piccini I, Rao J, Quaranta R, Zeuschner D, Malan D, Kim KP, Ropke A, Sasse P, Arauzo-Bravo M, Seebohm G, Scholer H, Fabritz L, Kirchhof P, Muller FU, Greber B (2015) Universal cardiac induction of human pluripotent stem cells in two and three-dimensional formats: implications for in vitro maturation. Stem Cells 33:1456–1469. https://doi.org/10.1002/stem.1964

    Article  CAS  PubMed  Google Scholar 

  63. Zorzano A, Liesa M, Sebastian D, Segales J, Palacin M (2010) Mitochondrial fusion proteins: dual regulators of morphology and metabolism. Semin Cell Dev Biol 21:566–574. https://doi.org/10.1016/j.semcdb.2010.01.002

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Martin Förster, for his support during FCM procedures and Beate Schulze for her technical assistance, Department of Cardiology, University Hospital Jena.

Funding

This study was supported by the Interdisciplinary Center for Clinical Research (IZKF, J55) of the Medical Faculty, University of Jena.

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Correspondence to Mohamed M. Bekhite.

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Bekhite, M.M., González Delgado, A., Menz, F. et al. Longitudinal metabolic profiling of cardiomyocytes derived from human-induced pluripotent stem cells. Basic Res Cardiol 115, 37 (2020). https://doi.org/10.1007/s00395-020-0796-0

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