Wang Yi, Nguyen Thomas, He Qingan, Has Oliver, Forouzesh Kiarash, Eom Dae Seok
Department of Developmental and Cell Biology, University of California, Irvine, United States.
Center for Complex Biological Systems, University of California, Irvine, United States.
Elife. 2025 Aug 6;13:RP97400. doi: 10.7554/eLife.97400.
The skin, the largest organ, functions as a primary defense mechanism. Epidermal stem cells supply undifferentiated keratinocytes that differentiate as they migrate toward the outermost skin layer. Although such a replenishment process is disrupted in various human skin diseases, its underlying mechanisms remain elusive. With high-resolution live imaging and in vivo manipulations, we revealed that Notch signaling between keratinocytes is mediated by signaling filopodia called cytonemes and is essential for proper keratinocyte differentiation and proliferation. Inhibiting keratinocyte cytonemes reduced Notch expression within undifferentiated keratinocytes, leading to abnormal differentiation and hyperproliferation, resembling human skin disease phenotypes. Overproduction of Interleukin (IL)-17 signal, associated with skin diseases like psoriasis, induces psoriatic phenotypes by reducing cytoneme extension in zebrafish. Our study suggests that intercellular signaling between keratinocytes through cytonemes is critical for epidermal maintenance, and its misregulation could be an origin of human skin diseases.
皮肤作为最大的器官，发挥着主要防御机制的作用。表皮干细胞提供未分化的角质形成细胞，这些角质形成细胞在向最外层皮肤迁移的过程中发生分化。尽管这种补充过程在各种人类皮肤疾病中受到破坏，但其潜在机制仍不清楚。通过高分辨率实时成像和体内操作，我们发现角质形成细胞之间的Notch信号由称为细胞线的信号丝状伪足介导，并且对于适当的角质形成细胞分化和增殖至关重要。抑制角质形成细胞的细胞线会降低未分化角质形成细胞内的Notch表达，导致异常分化和过度增殖，类似于人类皮肤疾病的表型。与银屑病等皮肤病相关的白细胞介素（IL）-17信号的过量产生，通过减少斑马鱼中的细胞线延伸而诱导银屑病表型。我们的研究表明，角质形成细胞之间通过细胞线进行的细胞间信号传导对于表皮维持至关重要，其失调可能是人类皮肤疾病的根源。
