iPSC-Derived Vascularized Human Lung Organoids and Interaction Between Lung Endothelial Cells and Alveolar Epithelial Cells

iPSC 衍生的血管化人肺类器官以及肺内皮细胞和肺泡上皮细胞之间的相互作用

• 批准号: 10673199
• 负责人: Asrar B. Malik
• 金额: $ 73.06万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673199
• 关键词: 2019-nCoV; 3-Dimensional; ACE2; Address; Affect; Affinity; Alveolar; Alveolus; Anastomosis - action; Blood Vessels; COVID-19 pandemic; Cell Death; Cell Proliferation; Cells; Circulation; Cues; Data; Development; Disease model; Distal; Endothelial Cells; Endothelium; Epithelial Cells; Epithelium; Exclusion; Generations; Genes; Health; Homeostasis; Human; Implant; In Vitro; Infection; Inflammation; Inflammatory; Injury; Kidney; Lung; Lung diseases; Lung infections; Macrophage; Mediating; Metabolism; Modeling; Molecular; Morphogenesis; Mus; Natural regeneration; Nutrient; Organoids; Pathology; Pathway interactions; Pattern; Peptides; Perfusion; Phenotype; Pluripotent Stem Cells; Population; Publishing; Resolution; Role; Selection for Treatments; Signal Pathway; Signal Transduction; Structure; Structure of parenchyma of lung; Study models; System; Testing; Therapeutic; Type II Epithelial Receptor Cell; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelium; Vascularization; WNT Signaling Pathway; alveolar epithelium; alveolar type II cell; capsule; cell type; drug efficacy; drug testing; endothelial stem cell; epithelial stem cell; gene regulatory network; human disease; human model; implantation; induced pluripotent stem cell; inflammatory lung disease; interest; lung injury; lung maturation; lung microvascular endothelial cells; lung regeneration; migration; monocyte; neutrophil; novel; novel therapeutics; post SARS-CoV-2 infection; prevent; progenitor; pulmonary function; receptor; response; single-cell RNA sequencing; stem cells

ABSTRACT Human induced pluripotent stem cells (iPSCs) can be used to generate 3-dimensional lung organoid structures. However, most lung organoid studies have focused on human iPSC-derived lung epithelial subtypes. They have not to date included human iPSC-derived endothelial cells and systematically addressed the critical role of lung vascular endothelial cells and vascular perfusion itself in the generation and maturation of lung organoids which model human lung structures. The alveolar units consist of two predominant cell types – epithelial cells (EpiC)(40-45% of total cells) and endothelial cells (EC) (45-50% of total cells). Our key Supporting Data support the critical and heretofore underestimated role of human lung vascular endothelial cells in guiding differentiation of human lung epithelial progenitor cells and formation of vascularized human lung organoid. We propose to use this novel platform generated by integration of hiPSC-derived epithelial and endothelial cells to address the following aims: Aim 1 tests the hypothesis that endothelial cell-derived angiocrine signals in lung organoids activate Wnt signaling and mediate the maturation of lung alveolar units and the corollary hypothesis that reciprocal epicrine signaling of EpiC regulates lung EC fate, generation of recently described specific lung EC populations and lung microvessel patterning at the level of alveoli. Aim 2 will test the hypothesis that the vascularized and perfused human lung organoid serves as a translationally relevant reductionist model for teasing apart the elusive signaling and molecular mechanisms of inflammatory injury at the level of the alveolar unit and resolution of injury. Aim 3 will test the hypothesis that lung EC signaling through the upregulation of ACE2 in alveolar Type II epithelial cells promotes SARS-CoV-2 entry and infection of lungs. Together the proposed studies through their focus on lung EC and vascularization of human lung organoid and incorporation of alveolar epithelial cells in this system will uncover fundamental mechanisms of how the vascularized alveolar unit functions in health to maintain homeostasis and how defective cross-talk between EC and alveolar epithelial cells contributes to inflammatory lung disease.

抽象的 人类诱导多能干细胞 (iPSC) 可用于生成 3 维肺类器官 然而，大多数肺类器官研究都集中在人类 iPSC 衍生的肺上皮亚型上。 迄今为止，他们尚未纳入人类 iPSC 衍生的内皮细胞并系统地解决关键问题 肺血管内皮细胞和血管灌注本身在肺的生成和成熟中的作用 模拟人类肺结构的类器官由两种主要细胞类型组成。 上皮细胞 (EpiC)（占细胞总数的 40-45%）和内皮细胞 (EC)（占细胞总数的 45-50%）。 支持数据支持人类肺血管内皮细胞的关键且迄今为止被低估的作用 指导人肺上皮祖细胞分化和血管化人肺形成的细胞 我们建议使用这种通过整合 hiPSC 衍生的上皮细胞和 内皮细胞的目的是为了实现以下目标： 目标 1 检验内皮细胞来源的假设 肺类器官中的血管分泌信号激活 Wnt 信号传导并介导肺泡单位的成熟 EpiC 的相互外分泌信号调节肺 EC 命运的推论假设，最近产生 描述了特定的肺 EC 群体和肺泡水平的肺微血管模式，目标 2 将进行测试。 血管化和灌注的人肺类器官作为翻译相关的假设 还原论模型用于梳理难以捉摸的信号传导和炎症损伤的分子机制 目标 3 将检验肺 EC 信号传导的假设。 肺泡 II 型上皮细胞中 ACE2 的上调促进 SARS-CoV-2 进入肺部并感染。 拟议的研究通过关注肺内皮细胞和人肺类器官的血管化以及 将肺泡上皮细胞纳入该系统将揭示肺泡上皮细胞如何进行的基本机制 血管化肺泡单位在健康中发挥维持稳态的功能以及 EC 之间如何有缺陷的串扰 肺泡上皮细胞导致炎症性肺部疾病。