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Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis

机译：适应性血液动力学内皮细胞，用于有机组织和肿瘤发生

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摘要

The transient reactivation of ETV2 in adult human endothelial cells reprograms these cells to become adaptable vasculogenic endothelia that in three-dimensional matrices self-assemble into vascular networks that can transport blood and physiologically arborize organoids and decellularized tissues.Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration(1,2). 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 lumens(4,5). 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.
机译：成年人内皮细胞ETV2的瞬态再活化重新编程这些细胞，使其成为适应性血管生成内皮，其在三维基质中自组装成可以运输血液和生理学上的血管网络，并且脱细胞化组织。采用组织特异性特征指示器官发展和再生（1,2）。这种适应性在培养的成人内皮细胞中丢失，其不会以有机型方式血管形成组织。在此，我们表明胚胎限制的ETS变体转录因子2（ETV2）（3）在培养的血清三维基质中培养的成熟人内皮细胞中的瞬态再活化由层蛋白，哺乳蛋白和IV型的混合物组成胶原蛋白（LEC矩阵）'重置这些内皮细胞至适应性，血管原性细胞，其形成令灌注和塑料血管玻璃。通过染色质重塑，ETV2诱导小微分途径，包括RAP1的激活，促进耐用腔（4,5）的形成。在三维基质中 - 没有生物印刷的支架 - “复位”血管内皮细胞（R-VECs）的约束，自组装成稳定的微流体室内的稳定，多层和分支血管网络，其能够运输人类血液。在体内，R-VEC在小鼠中皮下植入自组织成持久的本质涂层血管，该容器在功能上吻合到宿主循环并表现出持久的图案化，没有畸形或血管瘤的证据。 R-VECs直接与三维共培养有机体内的细胞相互作用，除去需要用于片内系统所需的限制性合成半透膜，从而为血管化提供生理平台，我们称之为“器官” vascularnet'。 R-Vecs能够灌注葡萄糖响应胰岛素分泌的人胰岛素，血管化脱细胞大鼠肠道和树脂植物健康或癌症的人结肠有机体。使用单细胞RNA测序和表观遗传分析，我们证明R-VECS建立了一种以组织特异性方式差异调节和符合细胞体和肿瘤骨的适应性血管核心。我们的vascularnet模型将允许代谢，免疫和生理化学研究和筛网破译有机型内皮细胞和实质细胞之间的串扰，以鉴定内皮细胞异质性的决定因素，并且可能导致治疗器官修复和肿瘤靶向的进展。

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  • 来源
    《Nature》 |2020年第7825期|426-432|共7页
  • 作者

    Palikuqi Brisa; Duc-Huy T Nguyen; Li Ge; Schreiner Ryan; Pellegata Alessandro F.; Liu Ying; Redmond David; Geng Fuqiang; Lin Yang; Gomez-Salinero Jesus M.; Yokoyama Masataka; Zumbo Paul; Zhang Tuo; Kunar Balvir; Witherspoon Mavee; Han Teng; Tedeschi Alfonso M.; Scottoni Federico; Lipkin Steven M.; Dow Lukas; Elemento Olivier; Xiang Jenny Z.; Shido Koji; Spence Jason R.; Zhou Qiao J.; Schwartz Robert E.; De Coppi Paolo; Rabbany Sina Y.; Rafii Shahin;

  • 作者单位

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA|Weill Cornell Med Dept Ophthalmol Margaret Dyson Vis Res Inst New York NY USA;

    UCL Stem Cell & Regenerat Med Sect DBC Programme Great Ormond St Inst Chad Hearth London England;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornell Med Appl Bioinformat Core Dept Physiol & Biophys New York NY USA;

    Weill Cornell Med Genom Resources Core Facil New York NY USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornell Med Sandra & Edward Meyer Canc Ctr Weill Cornell Grad Sch Med Sci Dept Biochem & Med New York NY USA;

    Weill Cornell Med Sandra & Edward Meyer Canc Ctr Weill Cornell Grad Sch Med Sci Dept Biochem & Med New York NY USA;

    UCL Stem Cell & Regenerat Med Sect DBC Programme Great Ormond St Inst Chad Hearth London England;

    UCL Stem Cell & Regenerat Med Sect DBC Programme Great Ormond St Inst Chad Hearth London England;

    Weill Cornell Med Sandra & Edward Meyer Canc Ctr Weill Cornell Grad Sch Med Sci Dept Biochem & Med New York NY USA;

    Weill Cornell Med Sandra & Edward Meyer Canc Ctr Weill Cornell Grad Sch Med Sci Dept Biochem & Med New York NY USA;

    Weill Cornell Med Caryl & Israel Englander Inst Precis Med Inst Computat Biomed Dept Physiol & Biophys New York NY USA;

    Weill Cornell Med Genom Resources Core Facil New York NY USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Univ Michigan Dept Internal Med Sch Med Ann Arbor MI USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA|Wear Cornell Med Dept Physiol Biophys & Syst Biol New York NY USA;

    UCL Stem Cell & Regenerat Med Sect DBC Programme Great Ormond St Inst Chad Hearth London England|Great Ormond St Hosp Children NHS Fdn Trust Specialist Neonatal & Paediat Surg London England;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA|Hofstra Univ Bioengn Program DeMatteis Sch Engn & Appl Sci Hempstead NY USA;

    Weill Cornea Med Div Regenerat Med Ansary Stem Cell Inst Dept Med New York NY 10065 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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