1. Vascular cells improve functionality of human cardiac organoids
- Author
-
Holly K. Voges, Simon R. Foster, Liam Reynolds, Benjamin L. Parker, Lynn Devilée, Gregory A. Quaife-Ryan, Patrick R.J. Fortuna, Ellen Mathieson, Rebecca Fitzsimmons, Mary Lor, Christopher Batho, Janice Reid, Mark Pocock, Clayton E. Friedman, Dalia Mizikovsky, Mathias Francois, Nathan J. Palpant, Elise J. Needham, Marina Peralta, Gonzalo del Monte-Nieto, Lynelle K. Jones, Ian M. Smyth, Neda R. Mehdiabadi, Francesca Bolk, Vaibhao Janbandhu, Ernestene Yao, Richard P. Harvey, James J.H. Chong, David A. Elliott, Edouard G. Stanley, Sophie Wiszniak, Quenten Schwarz, David E. James, Richard J. Mills, Enzo R. Porrello, James E. Hudson, Voges, Holly K, Foster, Simon R, Reynolds, Liam, Parker, Benjamin L, Wiszniak, Sophie, Schwarz, Quenten, and Hudson, James E
- Subjects
cardiac organoid ,inflammation ,extracellular matrix ,endothelin-1 ,disease modeling ,LAMA5 ,PDGF ,General Biochemistry, Genetics and Molecular Biology ,endothelial cells - Abstract
Refereed/Peer-reviewed 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.
- Published
- 2023