title: Dual modulation of the mitochondrial permeability transition pore and redox signaling synergistically promotes cardiomyocyte differentiation from pluripotent stem cells.
abstract: BACKGROUND
  Cardiomyocytes that differentiate from pluripotent stem cells (PSCs) provide a crucial cellular resource for cardiac regeneration. The mechanisms of mitochondrial metabolic and redox regulation for efficient cardiomyocyte differentiation are, however, still poorly understood. Here, we show that inhibition of the mitochondrial permeability transition pore (mPTP) by Cyclosporin A (CsA) promotes cardiomyocyte differentiation from PSCs.
  
  
  RESULTS
  We induced cardiomyocyte differentiation from mouse and human PSCs and examined the effect of CsA on the differentiation process. The cardiomyogenic effect of CsA mainly resulted from mPTP inhibition rather than from calcineurin inhibition. The mPTP inhibitor NIM811, which does not have an inhibitory effect on calcineurin, promoted cardiomyocyte differentiation as much as CsA did, but calcineurin inhibitor FK506 only slightly increased cardiomyocyte differentiation. CsA-treated cells showed an increase in mitochondrial calcium, mitochondrial membrane potential, oxygen consumption rate, ATP level, and expression of genes related to mitochondrial function. Furthermore, inhibition of mitochondrial oxidative metabolism reduced the cardiomyogenic effect of CsA while antioxidant treatment augmented the cardiomyogenic effect of CsA.
  
  
  CONCLUSIONS
  Our data show that mPTP inhibition by CsA alters mitochondrial oxidative metabolism and redox signaling, which leads to differentiation of functional cardiomyocytes from PSCs.
authors.affiliation: Laboratory of Vascular Biology and Stem Cell, Korea Advanced Institute of Science and Technology.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Cho
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Heo
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Park
authors.forename: Sukhyun
authors.initials: S
authors.lastname: Song
authors.forename: Injune
authors.initials: I
authors.lastname: Kim
authors.forename: Yong-Mahn
authors.initials: YM
authors.lastname: Han
authors.forename: Jun K
authors.initials: JK
authors.lastname: Yamashita
authors.forename: Jae Boum
authors.initials: JB
authors.lastname: Youm
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D061252:Feeder Cells; D006801:Humans; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; C090438:(melle-4)cyclosporin
keywords: metabolism; mitochondria; myocytes; redox; stem cells