title: Growth of engineered human myocardium with mechanical loading and vascular coculture.
abstract: BACKGROUND
  The developing heart requires both mechanical load and vascularization to reach its proper size, yet the regulation of human heart growth by these processes is poorly understood.
  
  
  OBJECTIVE
  We seek to elucidate the responses of immature human myocardium to mechanical load and vascularization using tissue engineering approaches.
  
  
  RESULTS
  Using human embryonic stem cell and human induced pluripotent stem cell-derived cardiomyocytes in a 3-dimensional collagen matrix, we show that uniaxial mechanical stress conditioning promotes 2-fold increases in cardiomyocyte and matrix fiber alignment and enhances myofibrillogenesis and sarcomeric banding. Furthermore, cyclic stress conditioning markedly increases cardiomyocyte hypertrophy (2.2-fold) and proliferation rates (21%) versus unconditioned constructs. Addition of endothelial cells enhances cardiomyocyte proliferation under all stress conditions (14% to 19%), and addition of stromal supporting cells enhances formation of vessel-like structures by ≈10-fold. Furthermore, these optimized human cardiac tissue constructs generate Starling curves, increasing their active force in response to increased resting length. When transplanted onto hearts of athymic rats, the human myocardium survives and forms grafts closely apposed to host myocardium. The grafts contain human microvessels that are perfused by the host coronary circulation.
  
  
  CONCLUSIONS
  Our results indicate that both mechanical load and vascular cell coculture control cardiomyocyte proliferation, and that mechanical load further controls the hypertrophy and architecture of engineered human myocardium. Such constructs may be useful for studying human cardiac development as well as for regenerative therapy.
authors: Molecular and Cellular Biology Program, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, 815 Mercer St., Seattle, WA 98109, USA.
authors: Nathaniel L
authors: NL
authors: Tulloch
authors: Veronica
authors: V
authors: Muskheli
authors: Maria V
authors: MV
authors: Razumova
authors: F Steven
authors: FS
authors: Korte
authors: Michael
authors: M
authors: Regnier
authors: Kip D
authors: KD
authors: Hauch
authors: Lil
authors: L
authors: Pabon
authors: Hans
authors: H
authors: Reinecke
authors: Charles E
authors: CE
authors: Murry
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