Investigating the consequences of primary and paracrine-driven secondary senescence for melanocyte function in 2D and 3D living skin equivalents

有令人信服的证据表明，衰老会导致衰老。衰老已经在成纤维细胞中进行了广泛的研究，其在皮肤中的存在增加与晚期皮肤老化（例如皱纹、老化的弹性蛋白）和色素斑（例如黄褐斑）有关。初级黑素细胞衰老的后果相对而言研究不足，但最近的证据表明它是皮肤表皮中的主要衰老细胞（Victorelli等人，2019 EMBO in press）。此外，衰老的成纤维细胞和黑素细胞如何影响正常色素沉着和衰老表型相对未知。我们开发了一种3D成人活体皮肤等效物（LSE），它忠实地再现了真皮和分层表皮。包含10%（生理学相关的）衰老HDF产生表皮厚度的显著降低，并从根本上改变真皮内非衰老HDF的转录组（通过单细胞RNAseq; scRNAseq），表明原发性衰老和旁分泌驱动的继发性衰老是不同的终点。我们的目的是探讨衰老对黑素细胞和角质形成细胞功能的影响。

There is compelling evidence that senescence drives ageing. Senescence has been extensively investigated in fibroblasts, whose increased presence in skin has been linked to advanced skin ageing (e.g. wrinkles, aged elastin) and pigmented spots (e.g. melasma). The consequences of primary melanocyte senescence is comparatively underexplored but very recent evidence indicates it is the dominant senescent cell in the skin epidermis (Victorelli et al., 2019 EMBO in press). In addition, how senescent fibroblast and melanocytes effect normal pigmentation and the ageing phenotype is relatively unknown. We have developed a 3D adult, human living skin equivalent (LSE) that faithfully reproduces the dermis and a stratified epidermis. The inclusion of 10% (physiologically relevant) senescent HDFs produced a significant decrease in epidermal thickness and fundamentally changed the transcriptome of non-senescent HDFs within the dermis (via single cell RNAseq; scRNAseq), suggesting that primary senescence and paracrine-driven secondary senescence are distinct endpoints. We aim to explore the consequences of senescence on melanocyte and keratinocyte function in 2D and 3D.