1. Vascular cells improve functionality of human cardiac organoids.
- Author
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Voges HK, Foster SR, Reynolds L, Parker BL, Devilée L, Quaife-Ryan GA, Fortuna PRJ, Mathieson E, Fitzsimmons R, Lor M, Batho C, Reid J, Pocock M, Friedman CE, Mizikovsky D, Francois M, Palpant NJ, Needham EJ, Peralta M, Monte-Nieto GD, Jones LK, Smyth IM, Mehdiabadi NR, Bolk F, Janbandhu V, Yao E, Harvey RP, Chong JJH, Elliott DA, Stanley EG, Wiszniak S, Schwarz Q, James DE, Mills RJ, Porrello ER, and Hudson JE
- Subjects
- Humans, Pericytes metabolism, Signal Transduction, Organoids metabolism, Endothelial Cells, Myocytes, Cardiac metabolism
- Abstract
Crosstalk between cardiac cells is critical for heart performance. Here we show that vascular cells within human cardiac organoids (hCOs) enhance their maturation, force of contraction, and utility in disease modeling. Herein we optimize our protocol to generate vascular populations in addition to epicardial, fibroblast, and cardiomyocyte cells that self-organize into in-vivo-like structures in hCOs. We identify mechanisms of communication between endothelial cells, pericytes, fibroblasts, and cardiomyocytes that ultimately contribute to cardiac organoid maturation. In particular, (1) endothelial-derived LAMA5 regulates expression of mature sarcomeric proteins and contractility, and (2) paracrine platelet-derived growth factor receptor β (PDGFRβ) signaling from vascular cells upregulates matrix deposition to augment hCO contractile force. Finally, we demonstrate that vascular cells determine the magnitude of diastolic dysfunction caused by inflammatory factors and identify a paracrine role of endothelin driving dysfunction. Together this study highlights the importance and role of vascular cells in organoid models., Competing Interests: Declaration of interests R.J.M., J.E.H., G.A.Q.-R., and E.R.P. are listed as co-inventors on pending patents that relate to cardiac organoid maturation and cardiac regeneration therapeutics. E.R.P. and J.E.H. are listed as co-inventors on pending patents that relate to endothelial cells in 3D cardiac products. J.E.H. is a co-inventor on licensed patents relating to engineered heart muscle. R.J.M., E.R.P., and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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