Molecular pathways controlling alveolar epithelial remodeling in development and regeneration

呼吸系统发育的早期阶段，包括分支形态发生和细胞 血统承诺已被广泛研究，这导致了我们的显着增加， 了解气管和肺是如何被指定的，以及内胚层谱系是如何致力于 不同的上皮细胞命运然而，对发展的后期阶段知之甚少， 成熟，这是必要的，以形成空气血管界面的重要气体交换在 出生后肺肺发育的这些后期步骤涉及到细胞的急剧变化， 分化和形态，导致远端球囊的扩张和扩张， 这些囊最终分隔成肺泡以增加有效气体交换的表面积。 这些步骤的重要性通过这些形态学过程中的缺陷而突出， 尚不清楚的综合征包括支气管肺发育不良，可导致严重的 新生儿窘迫或死亡。尽管肺囊状形成和肺泡形成的重要性， 参与的分子途径和这些步骤所需的细胞重塑仍然存在， 不太了解。我们先前已经证明，I类组蛋白脱乙酰基酶1和2（HDAC 1 和-2）对于近端Sox 2+肺内胚层祖细胞的发育是必需的，导致 近端气道上皮分化的丧失。我们现在表明，I类HDAC，HDAC 3， 调节晚期肺上皮成熟和细胞重塑，这对于囊状形成和早期肺上皮成熟至关重要。 肺泡形成我们的初步数据表明，HDAC 3调节囊状和早期 通过抑制包括miR 17 -92簇的miRNA程序来促进肺泡形成。去- 在HDAC 3缺陷型肺上皮中miR 17 -92的抑制导致TGF-β信号传导的抑制， miR 17 -92靶向TGF-β途径的多个组分，包括TGF-β2、TGF-βR1、TGF-βR2。的 TGF-β信号传导活性的降低导致AT 1细胞无法扩散和重塑， 导致球囊/肺泡空气空间扩张不足和新生儿死亡。有趣的是，这些缺陷 与观察到的AT 1细胞规格或承诺的变化无关。初步数据 还表明HDAC 3调节肺泡上皮对成人肺损伤的反应。这些 这些发现将对我们理解表观遗传机制和细胞遗传学产生广泛的影响。 这是适当的晚期肺发育以及出生后修复和再生所需的重塑。

The early stages of respiratory system development including branching morphogenesis and cell lineage commitment have been studied extensively and this has led to a dramatic increase in our understanding of how the trachea and lungs are specified and how endodermal lineages commit to different epithelial cell fates. However, less is known about the late stages of development and maturation, which are required to form the air-vascular interface important for gas exchange in the postnatal lung. These later steps of lung development involve dramatic changes in cellular differentiation and morphology, resulting in the dilation and expansion of the distal saccules and eventual septation of these saccules into alveoli to increase surface area for efficient gas exchange. The importance of these steps is highlighted by defects in these morphological processes resulting in poorly understood syndromes including bronchopulmonary dysplasia, which can lead to severe neonatal distress or death. Despite the importance of lung sacculation and alveologenesis, the molecular pathways involved and the cellular remodeling that is required for these steps remains poorly understood. We have previously shown that the class I histone deacetylases 1 and 2 (HDAC1 and -2) are essential for development of the proximal Sox2+ lung endoderm progenitors, resulting in the loss of proximal airway epithelial differentiation. We now show that the class I HDAC, HDAC3, regulates late lung epithelial maturation and cellular remodeling essential for sacculation and early alveologenesis. Our preliminary data suggest that HDAC3 regulates sacculation and early alveologenesis through repression of a miRNA program including the miR17-92 cluster. De- repression of miR17-92 in HDAC3 deficient lung epithelium leads to inhibition of Tgf-β signaling as miR17-92 targets multiple components of the Tgf-β pathway including Tgf-β2, Tgf-βR1, Tgf-βR2. The resultant decrease in Tgf-β signaling activity leads to a failure of AT1 cells to spread and remodel, causing a lack of saccule/alveolar airspace expansion and neonatal death. Interestingly, these defects are not associated with an observed change in AT1 cell specification or commitment. Preliminary data also shows that HDAC3 regulates the alveolar epithelial response to injury in the adult lung. These findings will have a broad impact on our understanding of the epigenetic mechanisms and cellular remodeling required for proper late lung development as well as postnatal repair and regeneration.