title: Terminal differentiation, advanced organotypic maturation, and modeling of hypertrophic growth in engineered heart tissue.
abstract: BACKGROUND
  Cardiac tissue engineering should provide "realistic" in vitro heart muscle models and surrogate tissue for myocardial repair. For either application, engineered myocardium should display features of native myocardium, including terminal differentiation, organotypic maturation, and hypertrophic growth.
  
  
  OBJECTIVE
  To test the hypothesis that 3D-engineered heart tissue (EHT) culture supports (1) terminal differentiation as well as (2) organotypic assembly and maturation of immature cardiomyocytes, and (3) constitutes a methodological platform to investigate mechanisms underlying hypertrophic growth.
  
  
  RESULTS
  We generated EHTs from neonatal rat cardiomyocytes and compared morphological and molecular properties of EHT and native myocardium from fetal, neonatal, and adult rats. We made the following key observations: cardiomyocytes in EHT (1) gained a high level of binucleation in the absence of notable cytokinesis, (2) regained a rod-shape and anisotropic sarcomere organization, (3) demonstrated a fetal-to-adult gene expression pattern, and (4) responded to distinct hypertrophic stimuli with concentric or eccentric hypertrophy and reexpression of fetal genes. The process of terminal differentiation and maturation (culture days 7-12) was preceded by a tissue consolidation phase (culture days 0-7) with substantial cardiomyocyte apoptosis and dynamic extracellular matrix restructuring.
  
  
  CONCLUSIONS
  This study documents the propensity of immature cardiomyocytes to terminally differentiate and mature in EHT in a remarkably organotypic manner. It moreover provides the rationale for the utility of the EHT technology as a methodological bridge between 2D cell culture and animal models.
authors.affiliation: Department of Pharmacology, Georg-August-University Goettingen, Robert-Koch-Str 40, 37075 Goettingen, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Tiburcy
authors.forename: Michael
authors.initials: M
authors.lastname: Didié
authors.forename: Oliver
authors.initials: O
authors.lastname: Boy
authors.forename: Peter
authors.initials: P
authors.lastname: Christalla
authors.forename: Stephan
authors.initials: S
authors.lastname: Döker
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Naito
authors.forename: Bijoy Chandapillai
authors.initials: BC
authors.lastname: Karikkineth
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Michael
authors.initials: M
authors.lastname: Grimm
authors.forename: Monika
authors.initials: M
authors.lastname: Nose
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Anke
authors.initials: A
authors.lastname: Zieseniss
authors.forename: Doerthe M
authors.initials: DM
authors.lastname: Katschinksi
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Wolfram-Hubertus
authors.initials: WH
authors.lastname: Zimmermann
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D038081:Organogenesis; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000235:genetics; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D023822:Tissue Engineering