Endothelial cells are not required for specification of respiratory progenitors.
Endothelial cells are not required for specification of respiratory progenitors.
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DOI：
10.1016/j.ydbio.2017.05.003
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发表时间：
2017-07-01
影响因子：
2.7
通讯作者：
Shannon JM
中科院分区：
文献类型：
--
作者：
Havrilak JA;Melton KR;Shannon JM
间充质细胞和上皮细胞之间的相互作用影响多种组织中的器官发生，例如肺、胰腺、肝和神经系统。然而，肺间充质包含多种细胞类型，并且驱动肺发育早期事件的间充质细胞类型的精确鉴定仍然未知。已显示内皮细胞对于肺上皮图案形成、肺干细胞分化和损伤后再生的某些方面是必需的。此外，内皮细胞参与早期肝脏和胰腺发育。根据这些观察，我们推测内皮细胞也可能是呼吸野早期特化和随后肺芽形成所必需的。我们首先用小分子VEGFR抑制剂阻断E8.5培养的前肠中的VEGF信号传导，发现肺特化和芽形成没有改变。然而，当我们检查携带VEGFR Flk-1突变的E9.5小鼠胚胎（不发育内皮细胞）时，我们发现呼吸祖细胞特化受到阻碍。因为E9.5胚胎比对照同窝仔小得多，表明发育延迟的可能性，我们分离并培养了E8.5时突变体和对照胚胎的前肠，此时大小差异不明显。我们发现，无论是规范的呼吸领域和肺芽的形成发生在突变体和对照外植体。这些观察结果不受存在或不存在血清的影响。我们还观察到，肝规范和启动发生在内皮细胞的情况下，并在文化中的肝上皮细胞的扩张没有突变体和对照外植体之间的差异。与先前发表的结果一致，我们还发现，胰腺芽不维持在培养的前肠内皮细胞时，缺席。我们的观察结果支持这样的结论，即肺祖细胞和芽的早期特化不需要内皮细胞，并且在E9.5 Flk−/−胚胎中观察到的肺特化减少可能是由于在缺乏血管系统的情况下氧气，营养物质和其他因素的输送不足导致的发育延迟。
Crosstalk between mesenchymal and epithelial cells influences organogenesis in multiple tissues, such as lung, pancreas, liver, and the nervous system. Lung mesenchyme comprises multiple cell types, however, and precise identification of the mesenchymal cell type(s) that drives early events in lung development remains unknown. Endothelial cells have been shown to be required for some aspects of lung epithelial patterning, lung stem cell differentiation, and regeneration after injury. Furthermore, endothelial cells are involved in early liver and pancreas development. From these observations we hypothesized that endothelial cells might also be required for early specification of the respiratory field and subsequent lung bud initiation. We first blocked VEGF signaling in E8.5 cultured foreguts with small molecule VEGFR inhibitors and found that lung specification and bud formation were unaltered. However, when we examined E9.5 mouse embryos carrying a mutation in the VEGFR Flk-1, which do not develop endothelial cells, we found that respiratory progenitor specification was impeded. Because the E9.5 embryos were substantially smaller than control littermates, suggesting the possibility of developmental delay, we isolated and cultured foreguts from mutant and control embryos on E8.5, when no size differences were apparent. We found that both specification of the respiratory field and lung bud formation occurred in mutant and control explants. These observations were unaffected by the presence or absence of serum. We also observed that hepatic specification and initiation occurred in the absence of endothelial cells, and that expansion of the liver epithelium in culture did not differ between mutant and control explants. Consistent with previously published results, we also found that pancreatic buds were not maintained in cultured foreguts when endothelial cells were absent. Our observations support the conclusion that endothelial cells are not required for early specification of lung progenitors and bud initiation, and that the diminished lung specification seen in E9.5 Flk−/− embryos is likely due to developmental delay resulting from the insufficient delivery of oxygen, nutrients, and other factors in the absence of a vasculature.
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影响因子：
20.3
作者：
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通讯作者：
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影响因子：
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