Epithelial stem/progenitor cells as repair agents in diffuse alveolar damage

上皮干/祖细胞作为弥漫性肺泡损伤的修复剂

• 批准号: 10181019
• 负责人: Harold A Chapman
• 金额: $ 120.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10181019
• 关键词: Acids; Acute; Acute Lung Injury; Acute respiratory failure; Address; Adult Respiratory Distress Syndrome; Alveolar; Alveolar Cell Type I; Apoptosis; Area; Cell Differentiation process; Cells; Chronic; Clinical; Cytokeratin 17; Development; Diffuse; Distal; Endothelial Cells; Engraftment; Epithelial; Epithelial Cells; Equilibrium; Gases; Genes; Goals; Graft Survival; Histology; Homeostasis; Human; Hypoxia; Immunosuppression; In Vitro; Influenza; Injections; Injury; Lead; Lung; Lung diseases; Macaca; Methodology; Modeling; Molecular; Monkeys; Mus; Natural regeneration; Necrosis; Organ; Pathway interactions; Pharmacology; Phase; Primates; Process; Protocols documentation; Pulmonary Surfactant-Associated Protein C; Pulmonology; Replacement Therapy; Reporting; Research Personnel; Signal Transduction; Stress; Supportive care; Surface; Testing; Therapeutic; Toxic effect; Translations; Transplantation; Type II Epithelial Receptor Cell; Undifferentiated; alveolar epithelium; capillary bed; cell motility; cell replacement therapy; epithelial stem cell; epithelium regeneration; experimental study; functional improvement; improved; in vivo; induced pluripotent stem cell; influenza infection; injury and repair; lung hypoxia; lung injury; lung repair; migration; mouse model; notch protein; novel therapeutic intervention; progenitor; programs; pulmonary function; regeneration potential; regenerative; repaired; screening; self-renewal; stem; stem cell replacement; stem cells; tool; translation to humans

ABSTRACT The overall goal of this application is to develop a compelling rationale and workable methodology for the treatment of diffuse alveolar damage with transplanted human epithelial stem/progenitor cells capable of long term engraftment and improved organ function. Stem/progenitor replacement therapy is envisioned as a meaningful therapeutic adjunct in several clinical situations dominated by diffuse alveolar damage with epithelial loss: severe, acute lung injury, e.g. due to influenza or other causes of ARDS, as well as acute exacerbations of chronic fibrotic lung disease. Recent studies discussed in the application indicate effective alveolar regeneration, and thus improved lung function, requires both a first phase of expansion and migration of stem/progenitor cells to re-establish alveolar barriers followed by a second phase of differentiation of new barrier cells into mature type II (AEC2s) and type I alveolar cells. To develop a translational program for alveolar regeneration by transplantation of healthy lung epithelial stem/progenitor cells, three basic objectives are advanced: (1) Further delineation of the signaling programs by which endogenous human distal lung epithelial stem cells can be activated following major injury to establish new alveolar barriers and then differentiate to AEC2s. (2) In vitro development of pools of human distal (small airway and alveolar) epithelial stem cells, both endogenous and iPSC-derived, suitable for transplantation and directed differentiation in mice. Distal basal-like cells from human iPS cells using gene edited cells reporting surfactant protein C, cytokeratin 17 (Krt17), and NKX2.1 will be used to develop a workable protocol for directed differentiation after transplant. (3) Employ models of lung repair/regeneration approachable by transplantation as tools to assess the regenerative potential of human epithelial stem/progenitor cells. Macaque iPS cells suitable for transplantation into influenza-infected monkeys will be used as a primate model for therapy. It is anticipated that functional improvement in gas exchange and alveolar histology can be achieved in primates, providing both a rationale and methodology for stem/progenitor cells as adjunctive therapy after severe acute lung injury in humans.

抽象的 该应用程序的总体目标是为该应用开发令人信服的理由和可行的方法论 用移植的人上皮茎/祖细胞处理弥漫性肺泡损伤 术语植入和改善器官功能。茎/祖细胞替代疗法被认为是 在几种临床情况下，有意义的治疗辅助辅助因素以弥漫性肺泡损伤为主 上皮损失：严重，急性肺损伤，例如由于流感或其他ARD的原因以及急性 慢性纤维化肺部疾病的加剧。应用中讨论的最近的研究表明有效 肺泡再生，从而改善肺功能，需要膨胀和迁移的第一阶段 茎/祖细胞以重新建立肺泡屏障，然后第二阶段的分化 屏障细胞成成熟的II型（AEC2S）和I型肺泡细胞。制定翻译程序 通过移植健康肺上皮茎/祖细胞的牙槽再生，这三个基本目标 提前：（1）进一步描述内源性人类远端肺的信号传导程序 重大损伤后可以激活上皮干细胞以建立新的肺泡屏障，然后 与AEC2区分开。 （2）在体外开发人远端（小气道和肺泡）上皮的池 内源性和IPSC衍生的干细胞，适用于小鼠的移植和定向分化。 使用基因编辑的细胞报告表面活性剂蛋白C，细胞角蛋白的远端基底细胞。 17（KRT17）和NKX2.1将用于开发移植后定向分化的可行协议。 （3）采用可通过移植的肺修复/再生模型作为评估的工具 人上皮干/祖细胞的再生潜力。猕猴的IPS单元 移植到感染了流感的猴子中，将用作治疗的灵长类动物模型。预计 在灵长类动物中可以实现气体交换和肺泡组织学的功能改善，提供 严重急性肺损伤后，茎/祖细胞作为辅助治疗的基本原理和方法论 在人类中。