Wnt/β‐catenin signaling is critical for dedifferentiation of aged epidermal cells in vivo and in vitro
Wnt/β‐catenin signaling is critical for dedifferentiation of aged epidermal cells in vivo and in vitro
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DOI：
10.1111/j.1474-9726.2011.00753.x
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发表时间：
2012-02
期刊：
影响因子：
7.8
通讯作者：
Cuiping Zhang;Peng Chen;Yang Fei;Bo Liu;K. Ma;Xiaobing Fu;Zhili Zhao;T. Sun;Z. Sheng
中科院分区：
文献类型：
--
作者：
Cuiping Zhang;Peng Chen;Yang Fei;Bo Liu;K. Ma;Xiaobing Fu;Zhili Zhao;T. Sun;Z. Sheng
老化的表皮细胞具有去分化为干细胞样细胞的能力。然而，调节衰老表皮细胞去分化的信号仍不清楚。在这里，我们提供的证据表明 Wnt/β-连环蛋白对于体内和体外衰老表皮细胞去分化至关重要。将缺乏基底干细胞的人超薄表皮片中的一些老化表皮细胞移植到伤口上，去分化为CK19和β1整合素阳性但CK10阴性的干细胞样细胞。此外，Wnt/β-catenin通路在此过程中被激活。 Wnt-1、Wnt-4、Wnt-7a、β-连环蛋白、细胞周期蛋白 D1 和 c-myc 的表达增加。分泌性卷曲相关蛋白 1 是一种 Wnt/β-catenin 通路抑制剂，可阻断体内去分化。然后，将 Wnt/β-catenin 通路的激活剂（一种高度特异性的糖原合酶激酶 (GSK)-3β 抑制剂）添加到老化表皮细胞的培养基中。令人惊讶的是，我们发现该激活剂诱导了 CK19、β1 整合素、Oct4 和 Nanog 蛋白的更高表达。诱导老化的表皮细胞表现出高集落形成效率、长期增殖潜力，并且可以再生皮肤等同物（表皮干细胞也是如此）。这些结果表明Wnt/β-连环蛋白通路的激活诱导了衰老表皮细胞的去分化，这提出了一种生成表皮干细胞样细胞的新方法。
Aged epidermal cells have the capacity to dedifferentiate into stem cell‐like cells. However, the signals that regulate the dedifferentiation of aged epidermal cells remain unclear. Here, we provide evidence that Wnt/β‐catenin is critical for aged epidermal cell dedifferentiation in vivo and in vitro. Some aged epidermal cells in human ultrathin epidermal sheets lacking basal stem cells transplanted onto wounds dedifferentiated into stem cell‐like cells that were positive for CK19 and β1 integrin but negative for CK10. In addition, Wnt/β‐catenin pathway was activated during this process. There was increased expression of Wnt‐1, Wnt‐4, Wnt‐7a, β‐catenin, cyclin D1, and c‐myc. Secreted frizzled‐related protein 1, a Wnt/β‐catenin pathway inhibitor, blocked dedifferentiation in vivo. Then, the activator, a highly specific glycogen synthase kinase (GSK)‐3β inhibitor, of Wnt/β‐catenin pathway was added to the culture medium of aged epidermal cells. Surprisingly, we found that the activator induced higher expression of CK19, β1 integrin, Oct4, and Nanog proteins. The induced aged epidermal cells exhibited high colony‐forming efficiency, long‐term proliferative potential and could regenerate a skin equivalent (as do epidermal stem cells). These results suggested that activation of Wnt/β‐catenin pathway induced the dedifferentiation of aged epidermal cells, which suggest a new approach to generate epidermal stem cell‐like cells.