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- Title
Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity.
- Authors
Romeo, Sara G.; Secco, Ilaria; Schneider, Edoardo; Reumiller, Christina M.; Santos, Celio X. C.; Zoccarato, Anna; Musale, Vishal; Pooni, Aman; Yin, Xiaoke; Theofilatos, Konstantinos; Trevelin, Silvia Cellone; Zeng, Lingfang; Mann, Giovanni E.; Pathak, Varun; Harkin, Kevin; Stitt, Alan W.; Medina, Reinhold J.; Margariti, Andriana; Mayr, Manuel; Shah, Ajay M.
- 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. The microvasculature is critical for delivery of oxygen and metabolites throughout tissues. Here they use human blood vessel organoids to show that CTGF is a critical paracrine regulator of microvascular integrity that can restore pericyte coverage and vessel structure.
- Subjects
BLOOD vessels; ORGANOIDS; CELL metabolism; CHEMICAL inhibitors; ENDOTHELIAL cells; GLYCOLYSIS
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41326-2