College of Pharmacy, Seoul National University, Seoul, South Korea.
Cell Prolif. 2011 Dec;44(6):527-36. doi: 10.1111/j.1365-2184.2011.00786.x. Epub 2011 Oct 13.
Keratinocyte stem/progenitor cells (KSCs) are known to regenerate epidermal tissue which they perform through to their great regenerative capacity.
Because stimulation of resident KSCs may regenerate epidermal tissue, we devised a strategy to find an appropriate KSC activator from natural products and to develop it as a skin-rejuvenating agent.
Ent-16α, 17-dihydroxy-kauran-19-oic acid (DHK) isolated from Siegesbeckia pubescens exhibited a KSC-stimulating effect during screening of natural products. DHK increased proliferation and migration of KSCs using the Akt/ERK pathway. We further examined the mechanism of KSC stimulation and found that phosphorylation of Y1068 epithelial growth factor receptor (EGFR) was significantly increased. Functional inhibition of EGFR using neutralizing antibody and a chemical inhibitor, AG1478, attenuated DHK-induced KSC stimulation. In a 3D culture model of KSCs, DHK treatment significantly induced establishment of fully stratified epidermis and increased numbers of p63-positive cells. Likewise, DHK treatment significantly accelerated healing of epidermal wounds created by laser and dermatome, and increased p63-positive cells, in animal models.
Collectively, these results indicate that DHK regenerates epidermal tissue mainly through EGFR phosphorylation. As DHK has diverse advantages over recombinant growth factors for commercialization (that is long-term stability and skin permeability), DHK might be applied to wound-healing agents and to a basic materials used in cosmetics.
角质形成细胞干细胞（KSCs）已知能够通过其强大的再生能力再生表皮组织。
由于刺激驻留的 KSCs 可能会再生表皮组织，因此我们设计了一种策略，从天然产物中寻找合适的 KSC 激活剂，并将其开发为皮肤再生剂。
从苍耳中分离出的表-16α,17-二羟基-卡诺-19-酸（DHK）在天然产物筛选中表现出 KSC 刺激作用。DHK 通过 Akt/ERK 通路增加 KSCs 的增殖和迁移。我们进一步研究了 KSC 刺激的机制，发现表皮生长因子受体（EGFR）的 Y1068 磷酸化显著增加。使用中和抗体和化学抑制剂 AG1478 抑制 EGFR 的功能，可减弱 DHK 诱导的 KSC 刺激。在 KSCs 的 3D 培养模型中，DHK 处理显著诱导完全分层表皮的建立，并增加 p63 阳性细胞的数量。同样，在动物模型中，DHK 处理可显著加速激光和皮肤刀造成的表皮伤口的愈合，并增加 p63 阳性细胞的数量。
总之，这些结果表明 DHK 主要通过 EGFR 磷酸化来再生表皮组织。由于 DHK 在商业化方面具有比重组生长因子更多的优势（即长期稳定性和皮肤通透性），因此 DHK 可能应用于伤口愈合剂和化妆品的基础材料中。
