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

Sara 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 Mann, Varun Pathak, Kevin Harkin, Alan W Stitt, Reinhold J Medina, Andriana Margariti, Manuel Mayr, Ajay ShahMauro Giacca, Anna Zampetaki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Number of pages19
JournalNature Communications
Publication statusAccepted/In press - 30 Aug 2023

Keywords

  • Microvascular dysfunction, Cardiovascular Diseases, Blood Vessel Organoids, Induced Pluripotent Stem Cells, Glycolysis, Metabolic rewiring

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