Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625, Hannover, Germany.
Sci Rep. 2017 Nov 1;7(1):14803. doi: 10.1038/s41598-017-14790-2.
The differentiated cell types of the mature ureter arise from the distal ureteric bud epithelium and its surrounding mesenchyme. Uncommitted epithelial cells first become intermediate cells from which both basal and superficial cells develop. Mesenchymal progenitors give rise to separated layers of adventitial fibrocytes, smooth muscle cells and lamina propria fibrocytes. How progenitor expansion and differentiation are balanced is poorly understood. Here, we addressed the role of retinoic acid (RA) signaling in these programs. Using expression analysis of components and target genes, we show that pathway activity is restricted to the mesenchymal and epithelial progenitor pools. Inhibition of RA signaling in ureter explant cultures resulted in tissue hypoplasia with a relative expansion of smooth muscle cells at the expense of lamina propria fibroblasts in the mesenchyme, and of superficial cells at the expense of intermediate cells in the ureteric epithelium. Administration of RA led to a slight reduction of smooth muscle cells, and almost completely prevented differentiation of intermediate cells into basal and superficial cells. We identified cellular programs and transcriptional targets of RA signaling that may account for this activity. We conclude that RA signaling is required and sufficient to maintain mesenchymal and epithelial progenitors in early ureter development.
成熟输尿管的分化细胞类型来源于远端输尿管芽上皮及其周围的间充质。未分化的上皮细胞首先变成中间细胞，从中可以发育出基底细胞和表面细胞。间质祖细胞产生分离的外膜成纤维细胞、平滑肌细胞和固有层成纤维细胞层。祖细胞的扩增和分化如何平衡还知之甚少。在这里，我们研究了视黄酸（RA）信号在这些程序中的作用。通过对成分和靶基因的表达分析，我们表明该途径的活性仅限于间充质和上皮祖细胞库。在输尿管外植体培养物中抑制 RA 信号导致组织发育不良，平滑肌细胞相对扩张，间充质中的固有层成纤维细胞减少，输尿管上皮中的表面细胞减少。RA 的给药导致平滑肌细胞略有减少，并几乎完全阻止中间细胞分化为基底细胞和表面细胞。我们确定了 RA 信号转导的细胞程序和转录靶标，这些可能是其活性的原因。我们得出结论，RA 信号转导对于早期输尿管发育中维持间充质和上皮祖细胞是必需和充分的。
