TY - JOUR
T1 - Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity
AU - Romeo, Sara
AU - Secco, Ilaria
AU - Schneider, Edoardo
AU - Reumiller, Christina M.
AU - Santos, Celio X C
AU - Zoccarato, Anna
AU - Musale, Vishal
AU - Pooni, Aman
AU - Yin, Xiaoke
AU - Theofilatos, Konstantinos
AU - Cellone Trevelin, Silvia
AU - Zeng, Lingfang
AU - Mann, Giovanni
AU - Pathak, Varun
AU - Harkin, Kevin
AU - Stitt, Alan W
AU - Medina, Reinhold J
AU - Margariti, Andriana
AU - Mayr, Manuel
AU - Shah, Ajay
AU - Giacca, Mauro
AU - Zampetaki, Anna
PY - 2023/8/30
Y1 - 2023/8/30
N2 - 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.
AB - 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.
KW - Microvascular dysfunction, Cardiovascular Diseases, Blood Vessel Organoids, Induced Pluripotent Stem Cells, Glycolysis, Metabolic rewiring
M3 - Article
SN - 2041-1723
JO - Nature Communications
JF - Nature Communications
ER -
