TBX2-positive cells represent a multi-potent mesenchymal progenitor pool in the developing lung
TBX2-positive cells represent a multi-potent mesenchymal progenitor pool in the developing lung
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DOI：
10.1186/s12931-019-1264-y
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发表时间：
2019-12-23
影响因子：
5.8
通讯作者：
Kispert, Andreas
中科院分区：
文献类型：
--
作者：
Wojahn, Irina;Luedtke, Timo H.;Kispert, Andreas
背景资料：在胚胎哺乳动物肺中，间充质细胞既作为上皮细胞增殖、分化和形态发生的信号中心，又作为支持发育和成熟器官结构的多种分化细胞类型的来源。胚胎肺间充质是否是同质前体库以及它如何分化成不同的细胞谱系尚不清楚。我们以前已经表明，T-box转录因子基因Tbx 2在肺间充质的发展中小鼠肺，并需要在其中保持分支morphogenesis.Methods：我们确定Tbx 2/TBX 2表达在发展中小鼠肺原位杂交和免疫荧光分析。我们使用遗传谱系追踪方法，其中Cre系处于内源性Tbx 2控制元件（Tbx 2（cre））控制下，R26（mTmG）报告系追踪小鼠肺中的TBX 2阳性细胞。我们确定的命运TBX 2谱系的GFP报告和分化标志物在正常小鼠肺和肺中缺乏或过度表达TBX 2在肺mesenchyme.Results：我们表明，TBX 2强烈表达在发育中的小鼠肺间充质祖细胞的免疫荧光分析。在分化的平滑肌细胞和成纤维细胞中，TBX 2的表达仍然广泛，但强烈减少。在间皮细胞和内皮细胞中，表达更加多变和分散。所有的胎儿平滑肌细胞、内皮细胞和成纤维细胞都来源于TBX 2（+）祖细胞，而一半的间皮细胞有不同的起源。TBX 2表达细胞的命运是不改变TBX 2缺陷和TBX 2组成型过表达小鼠，但内皮细胞和平滑肌细胞的分布和丰度的改变过表达condition.Conclusion：肺间充质祖细胞的命运在很大程度上是独立的TBX 2。然而，TBX 2的连续和精确定时的下调是必要的，以允许支气管平滑肌细胞的适当分化和功能，并限制内皮分化。我们的工作表明TBX 2在早期肺间充质祖细胞中表达，并支持TBX 2在维持这些细胞的前体状态中的作用。
Background: In the embryonic mammalian lung, mesenchymal cells act both as a signaling center for epithelial proliferation, differentiation and morphogenesis as well as a source for a multitude of differentiated cell types that support the structure of the developing and mature organ. Whether the embryonic pulmonary mesenchyme is a homogenous precursor pool and how it diversifies into different cell lineages is poorly understood. We have previously shown that the T-box transcription factor gene Tbx2 is expressed in the pulmonary mesenchyme of the developing murine lung and is required therein to maintain branching morphogenesis.Methods: We determined Tbx2/TBX2 expression in the developing murine lung by in situ hybridization and immunofluorescence analyses. We used a genetic lineage tracing approach with a Cre line under the control of endogenous Tbx2 control elements (Tbx2(cre)), and the R26(mTmG) reporter line to trace TBX2-positive cells in the murine lung. We determined the fate of the TBX2 lineage by co-immunofluorescence analysis of the GFP reporter and differentiation markers in normal murine lungs and in lungs lacking or overexpressing TBX2 in the pulmonary mesenchyme.Results: We show that TBX2 is strongly expressed in mesenchymal progenitors in the developing murine lung. In differentiated smooth muscle cells and in fibroblasts, expression of TBX2 is still widespread but strongly reduced. In mesothelial and endothelial cells expression is more variable and scattered. All fetal smooth muscle cells, endothelial cells and fibroblasts derive from TBX2(+) progenitors, whereas half of the mesothelial cells have a different descent. The fate of TBX2-expressing cells is not changed in Tbx2-deficient and in TBX2-constitutively overexpressing mice but the distribution and abundance of endothelial and smooth muscle cells is changed in the overexpression condition.Conclusion: The fate of pulmonary mesenchymal progenitors is largely independent of TBX2. Nevertheless, a successive and precisely timed downregulation of TBX2 is necessary to allow proper differentiation and functionality of bronchial smooth muscle cells and to limit endothelial differentiation. Our work suggests expression of TBX2 in an early pulmonary mesenchymal progenitor and supports a role of TBX2 in maintaining the precursor state of these cells.