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: 10467249
• 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/10467249
• 关键词: 2019-nCoV; 3-Dimensional; ACE2; Address; Affect; Affinity; Alveolar; Alveolus; Anastomosis - action; Blood Circulation; Blood Vessels; COVID-19 pandemic; Cell Death; Cell Proliferation; Cells; Coculture Techniques; Cues; Data; Development; Disease model; Distal; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Generations; Genes; Health; Homeostasis; Human; Implant; In Vitro; Infection; Inflammation; Inflammatory; Injury; Kidney; Lung; Lung diseases; Lung infections; Mediating; Metabolism; Modeling; Molecular; Morphogenesis; Mus; Natural regeneration; Nutrient; Organoids; Pathology; Pathway interactions; Pattern; Peptides; Perfusion; Phenotype; Population; Publishing; Resolution; Role; 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; base; 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; macrophage; 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 人类诱导的多能干细胞（IPSC）可用于产生3维肺器官 结构。但是，大多数肺器官研究都集中在人IPSC衍生的肺上皮亚型上。 迄今为止，他们还没有包括人IPSC衍生的内皮细胞，并系统地解决了关键 肺血管内皮细胞和血管灌注本身在肺的发电和成熟中的作用 模拟人肺结构的器官。肺泡单元由两种主要的细胞类型组成 - 上皮细胞（EPIC）（占总细胞的40-45％）和内皮细胞（EC）（占总细胞的45-50％）。我们的钥匙 支持数据支持人类肺血管内皮的关键和迄今为止低估的作用 引导人肺上皮祖细胞的分化和血管化人肺的形成的细胞 器官。我们建议使用通过HIPSC衍生的上皮和 内皮细胞以解决以下目的：目标1检验了内皮细胞衍生的假设 肺类器官中的血管分泌信号激活Wnt信号并介导肺肺泡单位的成熟和 史诗般的互惠环源信号传导调节肺部命运，最近产生的推论假设 描述了特定的肺EC群体和肺微血管在肺泡的水平上形成。 AIM 2将测试 血管化和灌注的人肺器官的假设是翻译相关的假设 还原主义模型，用于分开炎症损伤的弹性信号传导和分子机制 肺泡单位的水平和损伤的分辨率。 AIM 3将检验肺EC信号传导的假设 ACE2在肺泡II型上皮细胞中的上调促进了SARS-COV-2进入和肺的感染。 通过关注肺EC和人类肺癌的血管化和血管形成，共同提出了研究 将肺泡上皮细胞掺入该系统将发现基本机制 血管化的牙槽单位在健康中起作用，以维持稳态以及EC之间的横话如何 肺泡上皮细胞有助于炎症性肺部疾病。