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塑是慢性肺的病因 疾病，但分子机制知之甚少。许多证据表明，启蒙和/或 慢性肺部疾病的进展与祖细胞功能障碍有关，因此表明 旨在调节上皮祖细胞的再生能力可提供治疗益处 对病人来说。在初步研究中，我们发现慢性阻塞性肺疾病患者肺组织中的肺泡2型(AT2)细胞丢失。 终末期IPF与远端气道基底细胞和分泌细胞的增生有关。远端呼吸道的来源 在肺泡祖细胞功能障碍的背景下，基底细胞及其对修复和重塑的贡献 不清楚。小鼠感染PR8流感病毒可导致基底样上皮细胞的募集，这些细胞可扩展到 重新填充耗尽的上皮细胞。我们的数据表明，感染肺的PR8激活环境导致 祖细胞潜能的扩大和基础干细胞样特性的获得。我们还发现， 依赖STAT3的细胞因子IL22在对PR8感染的早期反应中被诱导，并足以 在没有PR8感染的情况下，启动一个基本细胞分化计划。有趣的是，我们发现 IL22/STAT3信号通路增强上皮干细胞的作用可通过调控P53基因部分实现 剂量。基于这些数据，我们建议检验异位基底细胞分化的假说 在面对严重损伤时，远端呼吸道祖细胞的修复能力增强，并且这些 细胞命运的改变由局部产生的IL22调节，导致STAT3介导的 祖细胞潜能。此外，我们将检验STAT3对茎的影响的相关假设 细胞的潜能是通过抑制P53来调节的。这些假设将在以下目标中得到检验： 利用小鼠感染PR8流感病毒了解IL22/STAT3先天免疫的作用 调节祖细胞命运和组织修复或重塑的信号。具体目标将定义以下角色 IL22/STAT3信号在气道祖细胞调节中的作用(目标1)，研究STAT3 调节“干性”(目标2)和新生基础干细胞在修复和/或重建中的作用(目标3)。 这些目标的完成将为急性白血病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通路的持续激活如何促进组织重塑 慢性肺病的背景。我们期待着识别治疗靶点，从而导致 开发新的治疗方法来改变急慢性肺部疾病患者的预后。

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.