Mechanisms of stretch-mediated skin expansion at single cell resolution [ATAC-seq]

The ability of the skin to expand in response to stretching has, for decades, been exploited in reconstructive surgery. Several studies have investigated the response of stretching epidermal cells in vitro. However, it remains unclear how mechanical forces affect epidermal stem cell behaviour in vivo. Here, we develop a mouse model in which the temporal consequences of the stretching the skin epidermis can be studied. Using a multidisciplinary approach that combines clonal analysis and mathematical modelling, we show that mechanical force induces skin expansion by promoting the renewal of epidermal stem cells. This occurs through a structured response in which cell fates are coordinated locally by stem cells that switch between states primed for renewal or differentiation. Transcriptional and chromatin profiling identifies the gene regulatory networks modulated by mechanical force. Using a combination of pharmacological inhibition and several conditional gene loss-of-function mouse mutants, we dissect the signalling pathways that control force-mediated tissue expansion.

数十年来，皮肤受牵拉时的扩张能力已被应用于重建外科手术（reconstructive surgery）。已有多项研究在体外（in vitro）环境中探究了表皮细胞（epidermal cells）受牵拉后的反应。然而，目前仍不清楚机械力（mechanical forces）如何在体内（in vivo）影响表皮干细胞（epidermal stem cells）的行为。本研究构建了一种小鼠模型（mouse model），可用于研究皮肤表皮受牵拉后的时序性效应。本研究采用结合克隆分析（clonal analysis）与数学建模（mathematical modelling）的多学科研究方法，证实机械力通过促进表皮干细胞的自我更新，诱导皮肤扩张。该过程依托一套有序的响应机制：表皮干细胞可在预编程为自我更新或分化的状态间切换，从而在局部协调细胞命运（cell fates）。转录组与染色质分析（transcriptional and chromatin profiling）揭示了受机械力调控的基因调控网络（gene regulatory networks）。本研究联合使用药物抑制（pharmacological inhibition）手段与多种条件性基因功能缺失小鼠突变体（conditional gene loss-of-function mouse mutants），解析了调控力介导的组织扩张的信号通路（signalling pathways）。