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: 9355470
• 负责人: Harold A Chapman
• 金额: $ 94.83万
• 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/9355470
• 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; Injection of therapeutic agent; 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; Respiratory physiology; Signal Transduction; Stem cells; Stress; Supportive care; Surface; Testing; Therapeutic; Toxic effect; Translations; Transplantation; Type II Epithelial Receptor Cell; Undifferentiated; capillary bed; cell motility; experimental study; functional improvement; improved; in vivo; induced pluripotent stem cell; injury and repair; lung hypoxia; lung injury; lung repair; migration; mouse model; notch protein; novel therapeutic intervention; progenitor; programs; regenerative; repaired; screening; self-renewal; stem; 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以下方面开发令人信服的基本原理和可行的方法： 使用具有长期持续作用的移植人上皮干细胞/祖细胞治疗弥漫性肺泡损伤 足月植入和改善器官功能。干/祖细胞替代疗法被设想为 在以弥漫性肺泡损伤为主的几种临床情况下是有意义的治疗辅助 上皮损失：严重的急性肺损伤，例如由于流感或 ARDS 的其他原因，以及急性 慢性纤维化肺病的恶化。该申请中讨论的最新研究表明有效 肺泡再生，从而改善肺功能，需要第一阶段的扩张和迁移 干细胞/祖细胞重建肺泡屏障，然后是新细胞分化的第二阶段 屏障细胞分为成熟的 II 型 (AEC2s) 和 I 型肺泡细胞。开发翻译程序 通过移植健康肺上皮干细胞/祖细胞实现肺泡再生，三个基本目标 先进的：（1）进一步描述内源性人远端肺的信号传导程序 上皮干细胞可以在严重损伤后被激活，建立新的肺泡屏障，然后 区分为 AEC2。 (2) 人远端（小气道和肺泡）上皮池的体外发育 干细胞，包括内源性干细胞和 iPSC 衍生干细胞，适用于小鼠移植和定向分化。 使用报告表面活性蛋白 C、细胞角蛋白的基因编辑细胞，来自人 iPS 细胞的远端基底样细胞 17 (Krt17) 和 NKX2.1 将用于开发移植后定向分化的可行方案。 (3) 采用可通过移植实现的肺修复/再生模型作为工具来评估 人类上皮干/祖细胞的再生潜力。猕猴 iPS 细胞适用于 移植到感染流感的猴子中将用作灵长类动物模型的治疗。预计 灵长类动物可以实现气体交换和肺泡组织学的功能改善，提供 干/祖细胞作为严重急性肺损伤后辅助治疗的基本原理和方法 在人类中。