 Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesisBrisa Palikuqi,
Duc-Huy T. Nguyen,
Ge Li,
Ryan Schreiner,
Alessandro F. Pellegata,
Ying Liu,
David Redmond,
Fuqiang Geng,
Yang Lin,
Jesus M. Gómez-Salinero,
Masataka Yokoyama,
Paul Zumbo,
Tuo Zhang,
Balvir Kunar,
Mavee Witherspoon,
Teng Han,
Alfonso M. Tedeschi,
Federico Scottoni,
Steven M. Lipkin,
Lukas Dow,
Olivier Elemento,
Jenny Z. Xiang,
Koji Shido,
Jason R. Spence,
Qiao J. Zhou,
Robert E. Schwartz,
Paolo Coppi,
Sina Y. Rabbany and
Shahin Rafii ()
Nature, 2020, vol. 585, issue 7825, 426-432 Abstract: Abstract Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration1,2. This adaptability is lost in cultured adult endothelial cells, which do not vascularize tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2)3 in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) ‘resets’ these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens4,5. In three-dimensional matrices—which do not have the constraints of bioprinted scaffolds—the ‘reset’ vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call ‘Organ-On-VascularNet’. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting. Date: 2020 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:585:y:2020:i:7825:d:10.1038_s41586-020-2712-z Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-020-2712-z Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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