Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity

Sara G. Romeo, Ilaria Secco, Edoardo Schneider, Christina M. Reumiller, Celio X. C. Santos, Anna Zoccarato, Vishal Musale, Aman Pooni, Xiaoke Yin, Konstantinos Theofilatos, Silvia Cellone Trevelin, Lingfang Zeng, Giovanni E. Mann, Varun Pathak, Kevin Harkin, Alan W. Stitt, Reinhold J. Medina, Andriana Margariti, Manuel Mayr, Ajay M. Shah, Mauro Giacca and Anna Zampetaki ()
Additional contact information
Sara G. Romeo: School of Cardiovascular & Metabolic Medicine and Sciences
Ilaria Secco: School of Cardiovascular & Metabolic Medicine and Sciences
Edoardo Schneider: School of Cardiovascular & Metabolic Medicine and Sciences
Christina M. Reumiller: School of Cardiovascular & Metabolic Medicine and Sciences
Celio X. C. Santos: School of Cardiovascular & Metabolic Medicine and Sciences
Anna Zoccarato: School of Cardiovascular & Metabolic Medicine and Sciences
Vishal Musale: School of Cardiovascular & Metabolic Medicine and Sciences
Aman Pooni: School of Cardiovascular & Metabolic Medicine and Sciences
Xiaoke Yin: School of Cardiovascular & Metabolic Medicine and Sciences
Konstantinos Theofilatos: School of Cardiovascular & Metabolic Medicine and Sciences
Silvia Cellone Trevelin: School of Cardiovascular & Metabolic Medicine and Sciences
Lingfang Zeng: School of Cardiovascular & Metabolic Medicine and Sciences
Giovanni E. Mann: School of Cardiovascular & Metabolic Medicine and Sciences
Varun Pathak: Queen’s University Belfast
Kevin Harkin: Queen’s University Belfast
Alan W. Stitt: Queen’s University Belfast
Reinhold J. Medina: Queen’s University Belfast
Andriana Margariti: Queen’s University Belfast
Manuel Mayr: School of Cardiovascular & Metabolic Medicine and Sciences
Ajay M. Shah: School of Cardiovascular & Metabolic Medicine and Sciences
Mauro Giacca: School of Cardiovascular & Metabolic Medicine and Sciences
Anna Zampetaki: School of Cardiovascular & Metabolic Medicine and Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The microvasculature plays a key role in tissue perfusion and exchange of gases and metabolites. In this study we use human blood vessel organoids (BVOs) as a model of the microvasculature. BVOs fully recapitulate key features of the human microvasculature, including the reliance of mature endothelial cells on glycolytic metabolism, as concluded from metabolic flux assays and mass spectrometry-based metabolomics using stable tracing of 13C-glucose. Pharmacological targeting of PFKFB3, an activator of glycolysis, using two chemical inhibitors results in rapid BVO restructuring, vessel regression with reduced pericyte coverage. PFKFB3 mutant BVOs also display similar structural remodelling. Proteomic analysis of the BVO secretome reveal remodelling of the extracellular matrix and differential expression of paracrine mediators such as CTGF. Treatment with recombinant CTGF recovers microvessel structure. In this work we demonstrate that BVOs rapidly undergo restructuring in response to metabolic changes and identify CTGF as a critical paracrine regulator of microvascular integrity.

Date: 2023
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DOI: 10.1038/s41467-023-41326-2

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