小柯机器人

2020年9月9日，《自然》杂志在线发表了美国威尔康奈尔医学中心Shahin Rafii及其团队的最新研究。他们研究发现内皮细胞血液动力学适应性有利于器官发育和肿瘤发生。

研究人员发现在无血清三维基质中培养的成熟人内皮细胞中，胚胎限制性ETS转录因子变体2（ETV2）被瞬时重新激活；该三维基质由混合的层粘连蛋白、牙本质素和IV型胶原蛋白组成（ LEC基质），其可将这些内皮细胞“重置”为适应性血管生成细胞，形成可灌注的可塑性血管丛。ETV2通过染色质重塑诱导肾小管生成途径，包括RAP1的激活，从而促进持久性管腔的形成。

在不受生物支架约束的三维矩阵中，“重置”的血管内皮细胞（R-VEC）在可扩展的微流室内自动组装成稳定的、多层的分支血管网络，其能够介导血液转运。在体内，通过皮下植入小鼠体内的R-VEC会自我组装成被持久性周细胞包被的血管，这些血管在功能上与宿主循环吻合，并具有稳定性，没有畸形或血管瘤生成的迹象。R-VEC与3维共培养类器官中的细胞直接相互作用，从而消除了芯片器官发育系统所需的限制性合成半透膜，因此为血管化提供了生理学平台，研究人员将其称为“器官- On-VascularNet”。

R-VEC可形成响应葡萄糖而分泌胰岛素的人胰岛、血管化去细胞大鼠肠道，并形成健康人或癌症患者的结肠类器官。使用单细胞RNA测序和表观遗传学分析，研究人员证明了R-VECs形成一种适应性血管生态位，其可以以组织特异性方式差异性地调节和适应类器官和类瘤。该Organ-On-VascularNet模型可以进行代谢、免疫和理化研究，并可以通过筛选以破译器官型内皮细胞与实质细胞之间的串扰，以揭示内皮细胞异质性的决定因素，并可能利于治疗性器官修复和肿瘤靶向的发展。

据悉，内皮细胞具有组织特异性，可介导器官发育和再生。培养的成年内皮细胞丧失了这种适应性，这种内皮细胞不具有以器官发育的方式促进组织血管化。

附：英文原文

Title: Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis

Author: Brisa Palikuqi, Duc-Huy T. Nguyen, Ge Li, Ryan Schreiner, Alessandro F. Pellegata, Ying Liu, David Redmond, Fuqiang Geng, Yang Lin, Jesus M. Gmez-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 De Coppi, Sina Y. Rabbany, Shahin Rafii

Issue&Volume: 2020-09-09

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.

DOI: 10.1038/s41586-020-2712-z

Source: https://www.nature.com/articles/s41586-020-2712-z

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