Epithelial progenitor cells for lung repair and regeneration

摘要 小气道上皮细胞功能障碍和结构组织重构是慢性肺损伤的特征性表现 疾病，但分子机制知之甚少。许多证据表明，启动和/或 慢性肺部疾病的进展与祖细胞功能障碍有关，因此， 旨在调节上皮祖细胞的再生能力， 给病人。在初步的研究中，我们发现，肺组织中肺泡2型（AT 2）细胞的损失， 终末期IPF与远端气道基底细胞和分泌细胞增生有关。远端气道来源 在肺泡祖细胞功能障碍的情况下，基底细胞及其对修复与重塑的贡献是 不清楚小鼠中的流感病毒（PR 8）感染导致基底样上皮细胞的募集，这些细胞扩增为 重新填充耗尽的上皮。我们的数据表明，感染肺的PR 8激活环境导致 祖细胞潜能的扩增和基底干细胞样特征的获得。我们还发现 STAT 3依赖性细胞因子IL 22在对PR 8感染的应答早期被诱导， 在没有PR 8感染的情况下启动基底细胞分化程序。有趣的是，我们发现 通过调节p53基因，IL 22/STAT 3信号转导增强上皮干细胞性可以部分表型化 剂量.基于这些数据，我们建议测试异位基底细胞分化的假设， 远端气道祖细胞的表达增强了严重损伤时的修复能力， 细胞命运的变化受IL 22的局部产生调节，导致STAT 3介导的细胞增殖。 祖细胞潜能。此外，我们将检验相关假设，即STAT 3在干细胞中的作用， 细胞效能通过抑制p53来介导。这些假设将在目标中进行测试， 利用PR 8流感病毒感染小鼠了解IL 22/STAT 3天然免疫的作用 在调节祖细胞命运和组织修复或重塑中的信号传导。具体目标将确定以下方面的作用： IL 22/STAT 3信号在气道祖细胞调节中的作用（目的1），研究STAT 3 调节“干细胞性”（Aim 2）和新生基底干细胞在修复和/或重塑中的作用（Aim 3）。 这些目标的完成将为急性损伤修复的细胞和分子机制提供新的见解。 肺损伤以及这些修复途径的持续激活如何有助于肺组织重塑。 慢性肺部疾病的背景。我们预期能够识别出可能导致 开发新疗法以改变急性和慢性肺病患者的结局。

ABSTRACT Small airway epithelial cell dysfunction and structural tissue remodeling are pathognomonic of chronic lung diseases, but molecular mechanisms are poorly understood. Much evidence indicates that initiation and/or progression of chronic lung disease is linked to progenitor cell dysfunction, hence suggesting that strategies aimed at modulating the regenerative capacity of epithelial progenitor cells could provide therapeutic benefits to patients. In preliminary studies we show that loss of alveolar type 2 (AT2) cells in lung tissue of patients with end-stage IPF is associated with distal airway basal and secretory cell hyperplasia. The source of distal airway basal cells and their contribution to repair vs remodeling in the setting of alveolar progenitor cell dysfunction is unclear. Influenza (PR8) virus infection in mice leads to recruitment of basal-like epithelial cells that expand to repopulate depleted epithelium. Our data suggest that the PR8-activated milieu of the infected lung leads to expansion of progenitor cell potency and acquisition of basal stem cell-like characteristics. We also found that the STAT3-dependent cytokine IL22 is induced early in the response to PR8 infection and was sufficient to initiate a program of basal cell differentiation in the absence of PR8 infection. Interestingly, we find that enhanced epithelial stemness by IL22/STAT3 signaling can be partially phenocopied by modulating p53 gene dosage. Based upon these data we propose to test the hypothesis that ectopic basal cell differentiation of distal airway progenitors enhances repair capacity in the face of severe injury and that these changes in cell fate are regulated by local production of IL22 leading to STAT3 mediated expansion of progenitor cell potency. Furthermore, we will test the related hypothesis that STAT3 effects of stem cell potency are mediated through suppression of p53. These hypotheses will be tested in aims that will take advantage of PR8 influenza virus infection in mice to understand roles for IL22/STAT3 innate immune signaling in regulation of progenitor cell fate and tissue repair or remodeling. Specific Aims will define roles for IL22/STAT3 signaling in regulation of airway progenitor cells (Aim 1), investigate mechanisms by which STAT3 regulates “stemness” (Aim 2) and roles for nascent basal stem cells in repair and/or remodeling (Aim 3). Completion of these aims will provide new insights into cellular and molecular mechanisms of repair in acute lung injury and how persistent activation of these repair pathways might contribute to tissue remodeling in the setting of chronic lung disease. We anticipate identification of therapeutic targets that could lead to the development of novel therapies to alter outcome in patients with acute and chronic lung disease.