Vascular cells improve functionality of human cardiac organoids

Voges, Holly K. and Foster, Simon R. and Reynolds, Liam and Parker, Benjamin L. and Devilée, Lynn and Quaife-Ryan, Gregory A. and Fortuna, Patrick R.J. and Mathieson, Ellen and Fitzsimmons, Rebecca and Lor, Mary and Batho, Christopher and Reid, Janice and Pocock, Mark and Friedman, Clayton E. and Mizikovsky, Dalia and Francois, Mathias and Palpant, Nathan J. and Needham, Elise J. and Peralta, Marina and Monte-Nieto, Gonzalo del and Jones, Lynelle K. and Smyth, Ian M. and Mehdiabadi, Neda R. and Bolk, Francesca and Janbandhu, Vaibhao and Yao, Ernestene and Harvey, Richard P. and Chong, James J.H. and Elliott, David A. and Stanley, Edouard G. and Wiszniak, Sophie and Schwarz, Quenten and James, David E. and Mills, Richard J. and Porrello, Enzo R. and Hudson, James E. (2023) Vascular cells improve functionality of human cardiac organoids. Cell Reports, 42 (5). p. 112322. ISSN 22111247

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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 beta (PDGFRbeta) 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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 10 Jul 2023 04:25
Last Modified: 10 Jul 2023 05:31

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