Keratinocyte Growth Factor (KGF) Modulates Epidermal Progenitor Cell Kinetics through Activation of p63 in Middle Ear Cholesteatoma
Keratinocyte Growth Factor (KGF) Modulates Epidermal Progenitor Cell Kinetics through Activation of p63 in Middle Ear Cholesteatoma
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DOI：
10.1007/s10162-018-0662-z
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发表时间：
2018-06-01
影响因子：
2.4
通讯作者：
Kojima, Hiromi
中科院分区：
文献类型：
--
作者：
Yamamoto-Fukuda, Tomomi;Akiyama, Naotaro;Kojima, Hiromi
基底干/祖细胞维持表皮的稳态。这种稳态的进行性紊乱被认为是上皮疾病（如中耳乳突瘤）发病的可能原因。在干/祖细胞调节的许多情况下，由周围细胞提供的细胞外信号的重要性是公认的。角质形成细胞生长因子（KGF）是一种间充质细胞源性旁分泌生长因子，特异性参与皮肤稳态;然而，KGF的过度表达诱导中耳乳突瘤。在这项研究中，两种胸苷类似物转移在不同的时间点，我们研究了过表达的KGF对干/祖细胞在体内的细胞动力学的影响。结果，在KGF转染标本的增厚上皮中检测到BrdU（+）EdU（+）细胞（干/祖细胞）。使用高分辨率显微镜使我们能够分析单个细胞核中p63的磷酸化水平，结果清楚地表明BrdU（+）EdU（+）细胞被认为是祖细胞。在KGF的过度表达中，祖细胞增殖的刺激被KGFR的酪氨酸激酶抑制剂SU 5402抑制。这些发现表明，KGF过表达可能会增加干/祖细胞增殖和阻断终末分化，导致上皮增生，这是典型的中耳乳突瘤。
The basal stem/progenitor cell maintains homeostasis of the epidermis. Progressive disturbance of this homeostasis has been implicated as a possible cause in the pathogenesis of epithelial disease, such as middle ear cholesteatoma. In many cases of stem/progenitor cell regulation, the importance of extracellular signals provided by the surrounding cells is well-recognized. Keratinocyte growth factor (KGF) is a mesenchymal-cell-derived paracrine growth factor that specifically participates in skin homeostasis; however, the overexpression of KGF induces middle ear cholesteatoma. In this study, two kinds of thymidine analogs were transferred at different time points and we investigated the effects of overexpressed KGF on the cell kinetics of stem/progenitor cells in vivo. As a result, BrdU(+)EdU(+) cells (stem/progenitor cells) were detected in the thickened epithelium of KGF-transfected specimens. The use of a high-resolution microscope enabled us to analyze the phosphorylated level of p63 in individual nuclei, and the results clearly demonstrated that BrdU(+)EdU(+) cells are regarded as progenitor cells. In the overexpression of KGF, the stimulation of progenitor cell proliferation was inhibited by SU5402, an inhibitor for tyrosine kinase of KGFR. These findings indicate that KGF overexpression may increase stem/progenitor cell proliferation and block terminal differentiation, resulting in epithelial hyperplasia, which is typical in middle ear cholesteatoma.