Lung regeneration and the stem cell niche

描述（由申请人提供）：在肺发育期间，FGF 10（成纤维细胞生长因子10）由远端间充质中的支气管旁平滑肌细胞（PSMC）祖细胞分泌，并激活远端上皮祖细胞中的经典WNT信号通路，以维持它们并维持它们的增殖。我们最近发表的研究结果表明，在胚胎肺中，PSMC祖细胞中的β-连环蛋白信号也是其维持和增殖所必需的。本研究的目的是确定该通路是否可以在成人中重新激活，以促进受损气道上皮的再上皮化。我们的初步研究结果表明，在萘损伤后不久，这种胚胎信号级联反应在成熟的PSMCs中重新激活。在萘损伤后，一些PSMC显示出活化的TOPGAL活性，作为活化的β-连环蛋白信号传导的读数，经历如通过BrdU掺入监测的大量增殖并重新表达Fgf 10。我们的数据表明，PSMC的这种旁分泌FGF 10信号传导对萘损伤后的上皮修复至关重要，可能是通过激活支气管肺泡管连接处（BADJ）的潜伏性支气管肺泡干细胞（BASC）。我们的初步数据还表明，在萘损伤后的上皮修复中，PSMCs有额外的细胞贡献。我们发现，成熟的PSMCs可以去分化，并进行间充质上皮转化（MET），直接有助于上皮修复过程。这表明PSMCs在萘损伤后的上皮修复中具有双重主要作用。假设：支气管旁平滑肌细胞的去分化和/或其祖细胞样表型的重现对于损伤后的上皮再生至关重要。目标1：确定萘损伤后周围（非上皮）“龛”细胞的分化状态及其在萘损伤后上皮再生中的潜在旁分泌作用。目的2：探讨萘损伤后大鼠肺间质平滑肌细胞的分化状态及其在上皮修复中的作用。公共卫生相关性：气道上皮重塑是慢性肺部疾病的常见病理特征，也是肺癌发生的诱发因素。因此，理解上皮维持和修复的细胞和分子机制对于开发用于治疗慢性肺病的改进的治疗模式是至关重要的。我们假设上皮损伤后，周围的非上皮细胞重新编程，直接或间接地分泌生长因子，促进上皮修复。

DESCRIPTION (provided by applicant): During lung development FGF10 (Fibroblast growth factor 10) is secreted by the parabronchial smooth muscle cell (PSMC) progenitors in the distal mesenchyme and activates the canonical WNT signaling pathway in the distally located epithelial progenitors to maintain them and sustain their proliferation. Our recently published results indicate that in the embryonic lung, (-catenin signaling in the PSMC progenitors is also essential for their maintenance and proliferation. The goal in this proposal is to determine if this pathway can be reactivated in adults to promote reepithelialization of damaged airway epithelium. Our preliminary findings illustrate reactivation of this embryonic signaling cascade in the mature PSMCs shortly after naphthalene injury. After naphthalene injury some of the PSMCs show activated TOPGAL activity, as a readout for activated (-catenin signaling, undergo massive proliferation as monitored by BrdU incorporation and reexpress Fgf10. Our data suggest that this paracrine FGF10 signaling by the PSMCs is critical for epithelial repair after naphthalene injury possibly by activating the latent bronchioalveolar stem cells (BASCs) at the Bronchio-alveolar duct junctions (BADJs). Our preliminary data also indicate an additional cellular contribution by the PSMCs in epithelial repair after naphthalene injury. We show that mature PSMCs can dedifferentiate and undergo Mesenchymal to Epithelial Transition (MET) to contribute directly to the epithelial repair process. This suggests a dual major role for the PSMCs in epithelial repair after naphthalene injury. Hypothesis: Dedifferentiation of parabronchial smooth muscle cells and/or their recapitulation of a progenitor like phenotype, is critical for epithelial regeneration after injury. Aim 1: To determine the differentiation status of the surrounding (non-epithelial) "niche" cells after naphthalene injury and their potential paracrine role in epithelial regeneration after naphthalene injury. Aim 2: To determine the differentiation status and cellular contribution of the PSMCs to epithelial repair after naphthalene injury. PUBLIC HEALTH RELEVANCE: Remodeling of the airway epithelium is a common pathological feature in chronic lung disease and a predisposing factor in the development of lung cancer. Accordingly, understanding cellular and molecular mechanisms of epithelial maintenance and repair are fundamental to the development of improved therapeutic modalities for the treatment of chronic lung disease. We hypothesize that after epithelial injury, the surrounding non-epithelial cells get reprogrammed to contribute, directly and indirectly be secreting growth factors, to the epithelial repair.