Derivation of lung mesenchymal lineages from the fetal mesothelium requires hedgehog signaling for mesothelial cell entry
Derivation of lung mesenchymal lineages from the fetal mesothelium requires hedgehog signaling for mesothelial cell entry
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DOI：
10.1242/dev.098079
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发表时间：
2013-11-01
期刊：
影响因子：
4.6
通讯作者：
Fine, Alan
中科院分区：
文献类型：
--
作者：
Dixit, Radhika;Ai, Xingbin;Fine, Alan
最近的研究表明，间皮祖细胞有助于发育器官的间充质谱系。覆盖的间皮在多大程度上有助于肺部发育仍不清楚。为了严格解决这个问题，我们采用Wt 1（CreERT 2/+）小鼠高保真谱系追踪后，确认Cre重组酶是间皮细胞特异性和忠实地再现内源性肾母细胞瘤1（Wt 1）基因表达。我们通过活体成像观察了WT 1（+）间皮细胞进入肺，并通过谱系标记在支气管平滑肌细胞、血管平滑肌细胞和结蛋白（+）成纤维细胞亚群中鉴定了它们的后代。这些谱系的衍生仅在早期肺发育期间用Cre重组酶活化观察到。使用器官培养物中的功能丧失测定和靶向间皮限制性刺猬功能丧失小鼠，我们证明了间皮细胞运动到肺中需要刺猬信号的直接作用。相比之下，hedgehog信号不需要胎儿间皮心脏进入。这些发现进一步支持了一种范例，其中间皮细胞是器官发生期间间充质谱系的祖细胞来源，并表明控制间皮细胞进入的信号是器官特异性的。
Recent studies have shown that mesothelial progenitors contribute to mesenchymal lineages of developing organs. To what extent the overlying mesothelium contributes to lung development remains unknown. To rigorously address this question, we employed Wt1(CreERT2/+) mice for high-fidelity lineage tracing after confirming that Cre recombinase was mesothelial specific and faithfully recapitulated endogenous Wilms' tumor 1 (Wt1) gene expression. We visualized WT1(+) mesothelial cell entry into the lung by live imaging and identified their progenies in subpopulations of bronchial smooth muscle cells, vascular smooth muscle cells and desmin(+) fibroblasts by lineage tagging. Derivation of these lineages was only observed with Cre recombinase activation during early lung development. Using loss-of-function assays in organ cultures, and targeted mesothelial-restricted hedgehog loss-of-function mice, we demonstrated that mesothelial cell movement into the lung requires the direct action of hedgehog signaling. By contrast, hedgehog signaling was not required for fetal mesothelial heart entry. These findings further support a paradigm wherein the mesothelium is a source of progenitors for mesenchymal lineages during organogenesis and indicate that signals controlling mesothelial cell entry are organ specific.