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Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Oct 03; Vol. 114 (40), pp. E8372-E8381. Date of Electronic Publication: 2017 Sep 15. - Publication Year :
- 2017
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Abstract
- The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies, where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of >10,000 organoids, we systematically optimize parameters, including extracellular matrix (ECM), metabolic substrate, and growth factor conditions, that enhance cardiac tissue viability, function, and maturation. Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Under these conditions, hPSC-CMs were refractory to mitogenic stimuli, and we found that key proliferation pathways including β-catenin and Yes-associated protein 1 (YAP1) were repressed. This proliferative barrier imposed by fatty acid metabolism in hCOs could be rescued by simultaneous activation of both β-catenin and YAP1 using genetic approaches or a small molecule activating both pathways. These studies highlight that human organoids coupled with higher-throughput screening platforms have the potential to rapidly expand our knowledge of human biology and potentially unlock therapeutic strategies.<br />Competing Interests: Conflict of interest statement: R.J.M., D.M.T., E.R.P., and J.E.H. are listed as coinventors on a pending patent held by The University of Queensland that relates to the Heart-Dyno device and maturation medium, which are described in this paper. R.J.M., G.A.Q.-R., E.R.P., and J.E.H. are listed as coinventors on a pending patent held by The University of Queensland that relates to the reactivation of cardiomyocyte cell cycle for cardiac regeneration. L.D., A.T.P., and Q.-D.W. are employees of AstraZeneca.
- Subjects :
- Adult
Animals
Cell Differentiation
DNA Damage
Humans
Male
Myocytes, Cardiac cytology
Organoids cytology
Pluripotent Stem Cells cytology
Rats, Sprague-Dawley
Biological Factors metabolism
Cell Cycle Checkpoints
Myocytes, Cardiac metabolism
Organoids metabolism
Pluripotent Stem Cells metabolism
Regeneration physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 114
- Issue :
- 40
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 28916735
- Full Text :
- https://doi.org/10.1073/pnas.1707316114