ΔNp63 controls stemness and inflammation in the adult epidermis

The p63 transcription factor is critical for epidermis formation in embryonic development, but its role in the adult epidermis is barely investigated. Here we show that acute genetic ablation of ΔNp63, the main p63 isoform, in the adult epidermis disrupts keratinocyte proliferation and self-maintenance and, unexpectedly, triggers an inflammatory psoriasis-like condition. Mechanistically, single-cell RNA sequencing revealed down-regulation of the cell cycle genes, up-regulation of differentiation markers, and induction of several pro-inflammatory pathways in ΔNp63-ablated keratinocytes. Intriguingly, ΔNp63-ablated cells disappear three weeks post-ablation, at the expense of the remaining non-ablated cells. This was not associated with active cell death mechanisms, but rather with reduced stemness and self-maintenance capacity. Indeed, in vivo wound healing assay, a physiological readout of the epidermal stem cell function, was largely impaired in the ablated skin. We found that the Wnt signaling pathway (Wnt5a, Wnt10a, Fzd6, Fzd10) and Col17a1 are the likely ΔNp63 effectors responsible for keratinocyte proliferation and stemness, while AP1 factors are responsible for excessive differentiation, and Il-1a, Il-18, Il-24 and Il-36γ for the suppression of inflammation. These data implicate ΔNp63 as a critical node that coordinates balanced epidermal homeostasis and suppression of inflammation in the adult epidermis, upstream of known regulatory pathways. ScRNA-seq of control or ΔNp63 epidermis at 1 day and 1 week

p63转录因子（transcription factor）在胚胎发育的表皮形成过程中发挥关键作用，但其在成体表皮中的功能却几乎未被深入研究。本研究发现，在成体表皮中对ΔNp63——p63的主要功能亚型——进行急性遗传消融，会破坏角质形成细胞（keratinocyte）的增殖与自我维持能力，且意外诱发了类似银屑病的炎症性病变。机制层面，单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）结果显示，在ΔNp63基因消融的角质形成细胞中，细胞周期相关基因表达下调，分化标志物表达上调，同时诱导了多条促炎信号通路的激活。值得注意的是，经ΔNp63基因消融的细胞在消融后三周逐渐消失，这一过程以残留的未消融细胞为代价。该现象并未伴随活跃的细胞死亡机制，而是源于干细胞干性（stemness）的降低与自我维持能力的减弱。事实上，作为表皮干细胞功能的生理检测指标，体内创伤愈合实验在消融组的皮肤中受到了显著损害。本研究发现，Wnt信号通路（Wnt signaling pathway）及其相关分子Wnt5a、Wnt10a、Fzd6、Fzd10与Col17a1，是介导角质形成细胞增殖与干细胞干性的ΔNp63潜在效应因子；而AP1转录因子（AP1 factors）则负责调控角质形成细胞的过度分化，IL-1α、IL-18、IL-24及IL-36γ则参与炎症的抑制过程。上述数据表明，ΔNp63作为关键调控节点，在已知调控通路的上游，协调成体表皮的稳态平衡与炎症抑制。本数据集包含对照组或ΔNp63基因消融后的成体表皮在消融后1天及1周时的单细胞RNA测序数据。