Inhibition of TGF-β signaling enables long-term proliferation of mouse primary epithelial stem/progenitor cells of the tympanic membrane and the middle ear mucosa.
Inhibition of TGF-β signaling enables long-term proliferation of mouse primary epithelial stem/progenitor cells of the tympanic membrane and the middle ear mucosa.
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DOI：
10.1038/s41598-023-31246-y
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发表时间：
2023-03-20
影响因子：
4.6
通讯作者：
Senoo, Makoto
中科院分区：
文献类型：
--
作者：
Yamamoto-Fukuda, Tomomi;Pinto, Filipa;Pitt, Keshia;Senoo, Makoto
中耳表面由鼓膜（TM）和中耳黏膜（MEM）组成。据报道，中耳炎、中耳胆脂瘤、中耳膜穿孔等多种疾病和病症可导致中耳功能障碍，最终导致高频听力损失。尽管TM和MEM上皮的干细胞/祖细胞在修复受损组织中具有重要作用，但由于缺乏长期扩增和维持干细胞/祖细胞的最佳方法，其在很大程度上仍未被表征。在这里，我们发现在低Ca2+条件下抑制TGF-β信号可以使TM和MEM的p63阳性上皮干细胞/祖细胞长期增殖，同时避免它们的恶性转化。事实上，我们的数据表明，扩增的TM和MEM干细胞/祖细胞对Ca2+刺激有反应，并分化为成熟的上皮细胞系，分别以细胞角蛋白（CK） 1/8/18或Bpifa1为标志。这些结果将使我们能够大量扩增TM和MEM的上皮干细胞/祖细胞进行大规模分析，并将增强小鼠模型在开发干细胞介导的治疗策略以治疗中耳疾病和病症中的应用。
The surface of the middle ear is composed of the tympanic membrane (TM) and the middle ear mucosa (MEM). A number of diseases and conditions such as otitis media, middle ear cholesteatoma, and perforation of the TM have been reported to cause dysfunction of the middle ear, ultimately leading to high-frequency hearing loss. Despite its importance in repairing the damaged tissues, the stem/progenitor cells of the TM and the MEM epithelia remains largely uncharacterized due, in part, to the lack of an optimal methodology to expand and maintain stem/progenitor cells long-term. Here, we show that suppression of TGF-β signaling in a low Ca2+ condition enables long-term proliferation of p63-positive epithelial stem/progenitor cells of the TM and the MEM while avoiding their malignant transformation. Indeed, our data show that the expanded TM and MEM stem/progenitor cells respond to Ca2+ stimulation and differentiate into the mature epithelial cell lineages marked by cytokeratin (CK) 1/8/18 or Bpifa1, respectively. These results will allow us to expand epithelial stem/progenitor cells of the TM and MEM in quantity for large-scale analyses and will enhance the use of mouse models in developing stem cell-mediated therapeutic strategies for the treatment of middle ear diseases and conditions.
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通讯作者：
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