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.

项目摘要/摘要 影响肺实质或肺泡的疾病会引起明显的发病率和 今天在美国的死亡率。这些疾病的治疗通常无效，并且 对新疗法的发展受到对 疾病发病机理的部分原因是无法从 患者。患者特异性肺泡上皮的无尽供应的推导 细胞将允许研究携带每个患者的原代细胞中的疾病发病机理 整个遗传背景，因此是新疗法的发展。这 申请提案，以续签一项重点是体外推导的长期项目 来自患者特异性诱导多能干细胞（IPSC）的肺上皮谱系的。 这种更新我们产生了功能成熟的肺泡的不足来源 来自IPSC的上皮2型细胞（AEC2S），我们已通过重新编程进行了设计 患者血液或皮肤标本。雇用由儿童和成人产生的IPSC 与表面活性剂基因中杂合突变引起的间质肺疾病， 我们建议对当前不可治疗的副肺肺疾病的发作进行建模 它的成立，可能是从有毒增益引发的AEC2功能障碍开始的事件 错误折叠蛋白的功能效应。通过三个目标，我们检验了以下假设 由携带表面活性剂途径突变的患者特异性IPSC产生的AEC2S 裸露的表面活性剂蛋白缺失导致蛋白质的干扰，迟到了 自噬，宽阔的肺泡祖细胞功能障碍和炎症激活的阻滞。

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