Derivation of lung epithelia from iPS cells for advanced disease modeling

从 iPS 细胞衍生肺上皮细胞用于晚期疾病模型

• 批准号: 10409819
• 负责人: Darrell N. Kotton
• 金额: $ 45.9万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409819
• 关键词: Adult; Affect; Air; Alveolar; Alveolar Cell; Alveolus; Attention; Autophagocytosis; Biogenesis; Biological Models; Blood; Breathing; Cell Differentiation process; Cell Maturation; Cells; Child; Childhood; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Derivation procedure; Development; Disease; Disease model; Distal; Engineering; Epithelial; Epithelial Cells; Event; Exhibits; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Grant; Homeostasis; Human; Hydroxychloroquine; In Vitro; Inflammatory; Inherited; Interstitial Lung Diseases; Knock-in; Life; Lung; Lung diseases; Methods; Modeling; Morbidity - disease rate; Mus; Mutation; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pluripotent Stem Cells; Population; Proteins; Proteomics; Publishing; Pulmonary Fibrosis; Pulmonary alveolar structure; STAT3 gene; Signal Transduction; Skin; Source; Specimen; Structure of parenchyma of lung; Testing; advanced disease; alveolar epithelium; base; design; directed differentiation; drug discovery; fibrotic interstitial lung disease; fibrotic lung disease; foot; gain of function; human pluripotent stem cell; in vitro Model; in vivo; induced pluripotent stem cell; loss of function; lung development; misfolded protein; mortality; mutant; novel; novel strategies; novel therapeutics; overexpression; pediatric patients; prevent; progenitor; proteostasis; response; self-renewal; stem cell function; stem cell model; surfactant; transcriptome; transcriptomics

Project Summary/Abstract Diseases affecting the lung parenchyma or alveoli cause significant morbidity and mortality in the US today. Treatments for these diseases are often ineffective and the development of novel therapeutics is hampered by an incomplete understanding of disease pathogenesis due in part to an inability to access living alveolar cells from patients. The derivation of an inexhaustible supply of patient-specific alveolar epithelial cells would allow studies of disease pathogenesis in primary cells carrying each patient’s entire genetic background, and consequently the development of new therapeutics. This application proposes to renew a long-standing project focused on the in vitro derivation of lung epithelial lineages from patient-specific induced pluripotent stem cells (iPSCs). In this renewal we generate an inexhaustible source of functionally mature alveolar epithelial type 2 cells (AEC2s) from iPSCs that we have engineered by reprogramming patient blood or skin specimens. Employing iPSCs generated from children and adults with interstitial lung diseases that arise from heterozygous mutations in surfactant genes, we propose to model the onset of a currently untreatable parenchymal lung disease at its inception, an event that likely begins with AEC2 dysfunction initiated by toxic-gain-of function effects of misfolded proteins. Through three aims we test the hypothesis that AEC2s generated from patient specific iPSCs carrying surfactant pathway mutations exhibit surfactant protein mistrafficking which leads to disrupted proteostasis, a late block in autophagy, broad alveolar progenitor dysfunction, and inflammatory activation.

项目概要/摘要 影响肺实质或肺泡的疾病会导致显着的发病率和 如今，这些疾病的治疗往往无效且死亡率很高。 对治疗性小说的不完全理解阻碍了治疗小说的发展 疾病发病机制部分是由于无法从活的肺泡细胞中获取 患者特异性肺泡上皮的取之不尽用之不竭的供应。 细胞将允许研究携带每个患者基因的原代细胞的疾病发病机制 整个遗传背景，从而开发新的疗法。 更新专注于体外衍生的长期项目的申请提案 来自患者特异性诱导多能干细胞（iPSC）的肺上皮谱系。 通过这种更新，我们产生了功能成熟的肺泡的取之不尽用之不竭的来源 我们通过重编程改造的来自 iPSC 的 2 型上皮细胞 (AEC2) 使用从儿童和成人身上产生的 iPSC。 由表面活性剂基因杂合突变引起的间质性肺疾病， 我们建议对目前无法治疗的实质肺病的发病进行建模 它的开始，这一事件可能始于由毒性增益引起的 AEC2 功能障碍 通过三个目标，我们检验了错误折叠蛋白质的功能影响。 由携带表面活性剂途径突变的患者特异性 iPSC 生成的 AEC2 冲浪表现出蛋白质错误运输，导致蛋白质稳态破坏，这是一种晚期的疾病 阻断自噬、广泛肺泡祖细胞功能障碍和炎症激活。

项目成果

Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells.

• DOI: 10.1016/j.stem.2020.07.022
• 发表时间: 2020-10-01
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Dost AFM;Moye AL;Vedaie M;Tran LM;Fung E;Heinze D;Villacorta-Martin C;Huang J;Hekman R;Kwan JH;Blum BC;Louie SM;Rowbotham SP;Sainz de Aja J;Piper ME;Bhetariya PJ;Bronson RT;Emili A;Mostoslavsky G;Fishbein GA;Wallace WD;Krysan K;Dubinett SM;Yanagawa J;Kotton DN;Kim CF
• 通讯作者: Kim CF

SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response.

• DOI: 10.1016/j.stem.2020.09.013
• 发表时间: 2020-12-03
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Huang J;Hume AJ;Abo KM;Werder RB;Villacorta-Martin C;Alysandratos KD;Beermann ML;Simone-Roach C;Lindstrom-Vautrin J;Olejnik J;Suder EL;Bullitt E;Hinds A;Sharma A;Bosmann M;Wang R;Hawkins F;Burks EJ;Saeed M;Wilson AA;Mühlberger E;Kotton DN
• 通讯作者: Kotton DN

Epithelial Stem and Progenitor Cells in Lung Repair and Regeneration.

• DOI: 10.1146/annurev-physiol-041520-092904
• 发表时间: 2021-02-10
• 期刊: Annual review of physiology
• 影响因子: 18.2

Heat Inactivation of Nipah Virus for Downstream Single-Cell RNA Sequencing Does Not Interfere with Sample Quality.

• DOI: 10.3390/pathogens13010062
• 发表时间: 2024-01-09
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Hume AJ;Olejnik J;White MR;Huang J;Turcinovic J;Heiden B;Bawa PS;Williams CJ;Gorham NG;Alekseyev YO;Connor JH;Kotton DN;Mühlberger E
• 通讯作者: Mühlberger E

Human iPSC-derived alveolar and airway epithelial cells can be cultured at air-liquid interface and express SARS-CoV-2 host factors.

• DOI: 10.1101/2020.06.03.132639
• 发表时间: 2020-06-04
• 期刊: bioRxiv : the preprint server for biology
• 作者: Abo, Kristine M;Ma, Liang;Villacorta-Martin, Carlos
• 通讯作者: Villacorta-Martin, Carlos