Lowell S, Jones P, Le Roux I, Dunne J, Watt F M
Keratinocyte Laboratory, Imperial Cancer Research Fund, London, WC2A 3PX, UK.
Curr Biol. 2000 May 4;10(9):491-500. doi: 10.1016/s0960-9822(00)00451-6.
Human epidermis is renewed throughout life from stem cells in the basal layer of the epidermis. Signals from the surrounding keratinocytes influence the differentiation of the stem cells, but the nature of the signals is unknown. In many developing tissues, signalling mediated by the transmembrane protein Delta1 and its receptor Notch1 inhibits differentiation. Here, we investigated the role of Delta-Notch signalling in postnatal human epidermis.
Notch1 expression was found in all living epidermal layers, but Delta1 expression was confined to the basal layer of the epidermis, with highest expression in those regions where stem cells reside. By overexpressing Delta1 or Delta(T), a truncated form of Delta1, in primary human keratinocytes and reconstituting epidermal sheets containing mixtures of Delta-overexpressing cells and wild-type cells, we found that cells expressing high levels of Delta1 or Delta(T) failed to respond to Delta signals from their neighbours. In contrast, wild-type keratinocytes that were in contact with neighbouring cells expressing Delta1 were stimulated to leave the stem-cell compartment and initiate terminal differentiation after a few rounds of division. Delta1 promoted keratinocyte cohesiveness, whereas Delta(T) did not.
We propose that high Delta1 expression by epidermal stem cells has three effects: a protective effect on stem cells by blocking Notch signalling; enhanced cohesiveness of stem-cell clusters, which may discourage intermingling with neighbouring cells; and signalling to cells at the edges of the clusters to differentiate. Notch signalling in epidermal stem cells thus differs from other progenitor cell populations in promoting, rather than suppressing, differentiation.
人类表皮在整个生命过程中由表皮基底层中的干细胞更新。来自周围角质形成细胞的信号影响干细胞的分化，但信号的性质尚不清楚。在许多发育中的组织中，由跨膜蛋白Delta1及其受体Notch1介导的信号传导会抑制分化。在此，我们研究了Delta-Notch信号传导在出生后人类表皮中的作用。
在所有有活力的表皮层中均发现有Notch1表达，但Delta1表达局限于表皮基底层，在干细胞所在区域表达最高。通过在原代人角质形成细胞中过表达Delta1或Delta(T)（Delta1的截短形式）以及重建含有过表达Delta细胞和野生型细胞混合物的表皮片，我们发现表达高水平Delta1或Delta(T)的细胞无法对来自其邻居的Delta信号作出反应。相反，与表达Delta1的相邻细胞接触的野生型角质形成细胞在经过几轮分裂后被刺激离开干细胞区室并开始终末分化。Delta1促进角质形成细胞的黏附性，而Delta(T)则无此作用。
我们提出表皮干细胞高表达Delta1有三种作用：通过阻断Notch信号对干细胞起保护作用；增强干细胞簇的黏附性，这可能阻止与相邻细胞混合；向簇边缘的细胞发出分化信号。因此，表皮干细胞中的Notch信号传导与其他祖细胞群体不同，它促进而非抑制分化。
