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Growth of Engineered Human Myocardium With Mechanical Loading and Vascular Coculture
Open accessAbstract
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.
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“but not pressure- and volume-based metrics directly representing pump performance of the heart”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [9]
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“engineered cardiac thin films, micro-tissues and strips allow the assessment of twitch force [9,12–19]”
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“Although hPSC-vCMs have been organized as monolayers and patches for electrophysiological assessment [6–8] and even surgical engraftment [9–11]”
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Liau, B. (2013) · DukeSpace (Duke University) · Cited by 1
Human pluripotent stem cells (hPSCs) for heart regeneration
Abilez, O. J., & Wu, J. C. (2014) · Elsevier eBooks · doi:10.1533/9780857096708.3.297
van den Heuvel, N. H. L. (2013) · Utrecht University Repository (Utrecht University)
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Eng, G. M. (2013) · doi:10.7916/d83n29m2
Brenner, C., David, R., & Franz, W. (2010) · Springer eBooks · doi:10.1007/978-90-481-9075-1_11
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Metadata
- Authors
- Tulloch, N. L., Muskheli, V., Razumova, M. V., Korte, F. S., Regnier, M., Hauch, K. D., Pabon, L., Reinecke, H., & Murry, C. E.
- Affiliations
- University of Washington (US)
- Venue
- Circulation Research
- Published
- 2011-06-24
- Volume
- 109
- Issue
- 1
- Pages
- 47-59
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3140796
- OpenAlex
- W2163068618
- Cited by
- 666
- References
- 72
- Citations by year
- 2026: 12 · 2025: 28 · 2024: 26 · 2023: 30 · 2022: 27 · 2021: 59 · 2020: 42 · 2019: 56 · 2018: 43 · 2017: 66 · 2016: 57 · 2015: 51 · 2014: 54 · 2013: 57 · 2012: 45
- FWCI
- 54.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1u24dk076126-01, 5r01hl064387-10)
- National Heart, Lung, and Blood Institute (R01-HL064387, R01 HL64387, T32HL007312, P01HL094374, R01HL084642)
- National Institute of General Medical Sciences (P01GM081619)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24-DK076126)
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- mechanical loading, vascularization, cardiomyocyte hypertrophy, cardiomyocyte proliferation, myofibrillogenesis, collagen matrix, endothelial cells, stromal cells, Starling curve, heart development, regenerative therapy, human embryonic stem cell-derived cardiomyocytes, iPSC-derived cardiomyocytes
- MeSH terms
- Animals, Animals, Newborn, Biomechanical Phenomena, Cells, Cultured, Extracellular Matrix, Humans, Rats, Inbred F344, Stress, Mechanical, Coculture Techniques, Tissue Engineering, Myocytes, Cardiac, Pluripotent Stem Cells, Endothelial Cells, Cell Proliferation, Rats, Embryonic Stem Cells
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