Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development
Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development
复制标题
DOI：
10.1242/jcs.235556
复制
发表时间：
2019-12-15
影响因子：
4
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
--
作者：
Fumoto, Katsumi;Takigawa-Imamura, Hisako;Kikuchi, Akira
在肺发育的后期，两种类型的肺泡上皮细胞--立方II型(AECII)和扁平I型(AECI)肺泡上皮细胞--形成远端肺囊。在这里，我们强调了表达MAP-微管亲和力调节激酶1(Mark1)的成纤维细胞是如何在肺发育的终末阶段(称为肺囊化)所必需的。在Mark1基因敲除(KO)小鼠中，远端球囊和AECI扁平显著受损。胎儿上皮细胞在与成纤维细胞共培养时产生肺泡样器，并分化为肺泡细胞。然而，在Mark1 KO成纤维细胞的存在下，细胞器的大小减小，AECI扁平化受到损害。在Mark1 KO成纤维细胞中，纤毛形成和Hedgehog途径受到抑制，导致I型胶原表达的丧失。I型胶原的加入恢复了与Mark1 KO成纤维细胞共培养的类器官细胞的AECI扁平化，并挽救了类器官细胞尺寸的减小。远端肺囊化的数学模型支持AECI扁平化对于球囊样结构的正确形成是必要的这一观点。这些结果表明，Mark1介导的成纤维细胞激活诱导AECI扁平化，从而调节远端肺囊化。
During the later stages of lung development, two types of pneumocytes, cuboidal type II (AECII) and flattened type I (AECI) alveolar epithelial cells, form distal lung saccules. Here, we highlight how fibroblasts expressing MAP-microtubule affinity regulating kinase 1 (Mark1) are required for the terminal stages of pulmonary development, called lung sacculation. In Mark1-knockout (KO) mice, distal sacculation and AECI flattening are significantly impaired. Fetal epithelial cells generate alveolar organoids and differentiate into pneumocytes when co-cultured with fibroblasts. However, the size of organoids decreased and AECI flattening was impaired in the presence of Mark1 KO fibroblasts. In Mark1 KO fibroblasts themselves, cilia formation and the Hedgehog pathway were suppressed, resulting in the loss of type I collagen expression. The addition of type I collagen restored AECI flattening in organoids co-cultured with Mark1 KO fibroblasts and rescued the decreased size of organoids. Mathematical modeling of distal lung sacculation supports the view that AECI flattening is necessary for the proper formation of saccule-like structures. These results suggest that Mark1-mediated fibroblast activation induces AECI flattening and thereby regulates distal lung sacculation.