Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis
Palikuqi Brisa,Nguyen Duc-Huy T,Li Ge et al. Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis.[J] .Nature, 2020, 585: 426-432.
Endothelial cells adopt tissue-specifc 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 scafolds—the 『reset』 vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfuidic 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 profling, we demonstrate that R-VECs establish an adaptive vascular niche that diferentially adjusts and conforms to organoids and tumoroids in a tissue-specifc 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 identifcation of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting.
內皮細胞具有組織特異性，可介導器官發育和再生。培養的成年內皮細胞喪失了這種適應性，這種內皮細胞不具有以器官發育的方式促進組織血管化。我們發現在無血清三維基質中培養的成熟人內皮細胞中，胚胎限制性ETS轉錄因子變體2（ETV2）被瞬時重新激活；該三維基質由混合的層粘連蛋白、牙本質素和IV型膠原蛋白組成（ LEC基質），其可將這些內皮細胞「重置」為適應性血管生成細胞，形成可灌注的可塑性血管叢。ETV2通過染色質重塑誘導腎小管生成途徑，包括RAP1的激活，從而促進持久性管腔的形成。在不受生物支架約束的三維矩陣中，「重置」的血管內皮細胞（R-VEC）在可擴展的微流室內自動組裝成穩定的、多層的分支血管網絡，其能夠介導血液轉運。在體內，通過皮下植入小鼠體內的R-VEC會自我組裝成被持久性周細胞包被的血管，這些血管在功能上與宿主循環吻合，並具有穩定性，沒有畸形或血管瘤生成的跡象。R-VEC與3維共培養類器官中的細胞直接相互作用，從而消除了晶片器官發育系統所需的限制性合成半透膜，因此為血管化提供了生理學平臺，我們將其稱為「器官- On-VascularNet」。R-VEC可形成響應葡萄糖而分泌胰島素的人胰島、血管化去細胞大鼠腸道，並形成健康人或癌症患者的結腸類器官。使用單細胞RNA測序和表觀遺傳學分析，我們證明了R-VECs形成一種適應性血管生態位，其可以以組織特異性方式差異性地調節和適應類器官和類瘤。該Organ-On-VascularNet模型可以進行代謝、免疫和理化研究，並可以通過篩選以破譯器官型內皮細胞與實質細胞之間的串擾，以揭示內皮細胞異質性的決定因素，並可能利於治療性器官修復和腫瘤靶向的發展。
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