Lung regeneration and the stem cell niche

描述(申请人提供)：在肺发育过程中，FGF10(成纤维细胞生长因子10)由位于远端间充质的支气管旁平滑肌细胞(PSMC)前体细胞分泌，并激活位于远端上皮祖细胞的典型的WNT信号通路，以维持它们和维持它们的增殖。我们最近发表的结果表明，在胚胎肺中，PSMC前体细胞中的(-catenin)信号对其维持和增殖也是必不可少的。这项建议的目标是确定这一途径是否可以在成人中重新激活，以促进受损呼吸道上皮的再上皮化。我们的初步发现表明，在萘损伤后不久，成熟的PSMCs中这种胚胎信号级联信号重新激活。在萘损伤后，一些PSMCs表现出激活的TOPGAL活性，作为激活的(-catenin)信号的读数，通过BrdU掺入监测经历了大量的增殖并重新表达Fgf10。我们的数据表明，PSMCs的这种旁分泌FGF10信号可能通过激活细支气管-肺泡管连接处(BADJ)的潜伏的细支气管肺泡干细胞(BASCs)而在萘损伤后的上皮修复中起关键作用。我们的初步数据还表明，PSMCs在萘损伤后的上皮修复中还有额外的细胞贡献。我们发现，成熟的PSMCs可以去分化，并经历间充质到上皮的转变(MET)，从而直接促进上皮修复过程。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：支气管周围平滑肌细胞的去分化和/或它们的祖细胞样表型的重现，是损伤后上皮再生的关键。目的1：探讨胰腺损伤后周围(非上皮性)“龛”细胞的分化状态及其旁分泌在上皮再生中的作用。目的：探讨胰腺损伤后PSMCs的分化状态及其在上皮修复中的细胞作用。公共卫生相关性：呼吸道上皮重塑是慢性肺部疾病的常见病理特征，也是肺癌发生的易感因素。因此，了解上皮维持和修复的细胞和分子机制是开发改进的慢性肺部疾病治疗方法的基础。我们假设，在上皮损伤后，周围的非上皮细胞被重新编程，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.