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.

中文翻译：

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Mark1通过I型肺细胞扁平化调节肺部发育中的远端空域扩张。

在肺发育的后期，两种类型的肺细胞形成了远端的肺囊泡，即立方II型（AECII）和扁平I型（AECI）肺泡上皮细胞。在这里，我们重点介绍了表达MAP-微管亲和力调节激酶1（Mark1）的成纤维细胞对于肺发育的最终阶段（称为肺接种）是必需的。在Mark1基因敲除（KO）小鼠中，远侧接种和AECI扁平化显着受损。与成纤维细胞共培养时，胎儿上皮细胞会产生肺泡类器官，并分化为肺细胞。但是，在Mark1 KO成纤维细胞的存在下，类器官的大小减小，并且AECI展平受到损害。在Mark1 KO成纤维细胞本身中，纤毛形成和Hedgehog途径受到抑制，导致I型胶原蛋白表达的损失。I型胶原蛋白的添加可恢复与Mark1 KO成纤维细胞共培养的类器官中的AECI扁平化，并挽救了减小的类器官的大小。远端肺移植的数学模型支持这样的观点，即AECI展平对于正确形成类似于球的结构是必要的。这些结果表明，Mark1介导的成纤维细胞活化可诱导AECI扁平化，从而调节远端肺部结扎。