Centre for Stem Cells and Regenerative Medicine, Faculty of Life Sciences & Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital, SE1 9RT, London, UK.
Division of Immunology, The Netherlands Cancer Institute, Postbus 90203, 1006 BE, Amsterdam, The Netherlands.
Sci Rep. 2019 Jul 25;9(1):10825. doi: 10.1038/s41598-019-47232-2.
Epidermal homeostasis depends on a balance between self-renewal of stem cells and terminal differentiation of their progeny. Notch signalling is known to play a role in epidermal stem cell patterning and differentiation. However, the molecular mechanisms are incompletely understood. Here we demonstrate dynamic patterns of Notch ligand and receptor expression in cultured human epidermis. Notch2 and 3 act together to promote differentiation, while Notch1 decreases stem cell proliferation. The Notch ligand Jagged1 triggers differentiation when presented on an adhesive substrate or on polystyrene beads and over-rides the differentiation inhibitory effect of cell spreading. In contrast, Delta-like 1 (Dll1) overexpression abrogates the pro-differentiation effect of Jagged1 in a cell autonomous fashion. We conclude that Dll1 expression by stem cells not only stimulates differentiation of neighbouring cells in trans, but also inhibits differentiation cell autonomously. These results highlight the distinct roles of different Notch receptors and ligands in controlling epidermal homeostasis.
表皮的稳态依赖于干细胞的自我更新和其后代的终末分化之间的平衡。已知 Notch 信号通路在表皮干细胞的模式形成和分化中发挥作用。然而，其分子机制尚不完全清楚。在这里，我们展示了 Notch 配体和受体在培养的人表皮中的动态表达模式。Notch2 和 Notch3 共同作用促进分化，而 Notch1 减少干细胞的增殖。当 Notch 配体 Jagged1 被呈现在黏附基质或聚苯乙烯珠上时，会引发分化，并且会克服细胞铺展的分化抑制作用。相比之下，Delta-like 1（Dll1）的过表达以细胞自主的方式消除 Jagged1 的促分化作用。我们得出结论，干细胞中 Dll1 的表达不仅刺激了相邻细胞的横向分化，而且还以细胞自主的方式抑制了分化。这些结果突出了不同 Notch 受体和配体在控制表皮稳态中的不同作用。
