Growth of Engineered Human Myocardium with Mechanical Loading and Vascular Co-culture
By N. Tulloch, V. Muskheli, M. Razumova, F. S. Korte, Michael Regnier, K. Hauch, Lil Pabon, H. Reinecke, Charles E. Murry. Circulation Research, 2011
655 citations recorded by the source corpus.
Rationale: 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. Methods and 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.
Subfields: Biomedical Engineering, Molecular Biology, Surgery
View Paper: https://www.semanticscholar.org/paper/b17ccb82cb5a88cfa5b0bfc9069b8f836ad746ba
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Citations in the corpus
- Production of De Novo Cardiomyocytes: Human Pluripotent Stem Cell Differentiation and Direct Reprogramming (2012, neutral): “Exercise via mechanical force (Tulloch et al., 2011) (which will likely be required for tissue constructs) has also been demonstrated to enhance maturation.”
- Engineering Adolescence: Maturation of Human Pluripotent Stem Cell-derived Cardiomyocytes (2014, methodology): “Our group was the first to adapt hydrogel-based tissue engineering techniques to generate human engineered cardiac tissue from hPSC-CMs.(65) The cells were cast in 3D collagen and basement membrane protein matrix followed by uniaxial mechanical stress conditioning.”