title: Role of alpha- and beta-adrenergic receptors in cardiomyocyte differentiation from murine-induced pluripotent stem cells.
abstract: OBJECTIVE
  Induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a promising source of cells for regenerative heart disease therapies, but progress towards their use has been limited by their low differentiation efficiency and high cellular heterogeneity. Previous studies have demonstrated expression of adrenergic receptors (ARs) in stem cells after differentiation; however, roles of ARs in fate specification of stem cells, particularly in cardiomyocyte differentiation and development, have not been characterized.
  
  
  METHODS
  Murine-induced pluripotent stem cells (miPSCs) were cultured in hanging drops to form embryoid bodies, cells of which were then differentiated into cardiomyocytes. To determine whether ARs regulated miPSC differentiation into cardiac lineages, effects of the AR agonist, epinephrine (EPI), on miPSC differentiation and underlying signalling mechanisms, were evaluated.
  
  
  RESULTS
  Treatment with EPI, robustly enhanced miPSC cardiac differentiation, as indicated by increased expression levels of cardiac-specific markers, GATA4, Nkx2.5 and Tnnt2. Although β-AR signalling is the foremost signalling pathway in cardiomyocytes, EPI-enhanced cardiac differentiation depended more on α-AR signalling than β-AR signalling. In addition, selective activation of α1-AR signalling with specific agonists induced vigorous cardiomyocyte differentiation, whereas selective activation of α2- or β-AR signalling induced no or less differentiation, respectively. EPI- and α1-AR-dependent cardiomyocyte differentiation from miPSCs occurred through specific promotion of CPC proliferation via the MEK-ERK1/2 pathway and regulation of miPS cell-cycle progression.
  
  
  CONCLUSIONS
  These results demonstrate that activation of ARs, particularly of α1-ARs, promoted miPSC differentiation into cardiac lineages via MEK-ERK1/2 signalling.
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Xiao-Li
authors: XL
authors: Li
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Di
authors: D
authors: Zeng
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.|Department of Emergency, Chinese PLA No.401 Hospital, Qingdao, 266071, China.
authors: Yan
authors: Y
authors: Chen
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Lu
authors: L
authors: Ding
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Wen-Ju
authors: WJ
authors: Li
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Ting
authors: T
authors: Wei
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Dong-Bo
authors: DB
authors: Ou
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Song
authors: S
authors: Yan
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Bin
authors: B
authors: Wang
authors: Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors: Qiang-Sun
authors: QS
authors: Zheng
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D058732:Embryoid Bodies / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D050991:GATA4 Transcription Factor / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5 / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020107:Troponin T / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; C484469:Nkx2-5 protein, mouse; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D020107:Troponin T; D004837:Epinephrine