Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Science.
Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, UK.
Br J Dermatol. 2024 Jun 20;191(1):92-106. doi: 10.1093/bjd/ljae061.
BACKGROUND: Extracellular matrices play a critical role in tissue structure and function and aberrant remodelling of these matrices is a hallmark of many age-related diseases. In skin, loss of dermal collagens and disorganization of elastic fibre components are key features of photoageing. Although the application of some small matrix-derived peptides to aged skin has been shown to beneficially affect in vitro cell behaviour and, in vivo, molecular architecture and clinical appearance, the discovery of new peptides has lacked a guiding hypothesis. OBJECTIVES: To identify, using protease cleavage site prediction, novel putative matrikines with beneficial activities for skin composition and structure. METHODS: Here, we present an in silico (peptide cleavage prediction) to in vitro (proteomic and transcriptomic activity testing in cultured human dermal fibroblasts) to in vivo (short-term patch test and longer-term split-face clinical study) discovery pipeline, which enables the identification and characterization of peptides with differential activities. RESULTS: Using this pipeline we showed that cultured fibroblasts were responsive to all applied peptides, but their associated bioactivity was sequence-dependent. Based on bioactivity, toxicity and protein source, we further characterized a combination of two novel peptides, GPKG (glycine-proline-lysine-glycine) and LSVD (leucine-serine-valine-aspartate), that acted in vitro to enhance the transcription of matrix -organization and cell proliferation genes and in vivo (in a short-term patch test) to promote processes associated with epithelial and dermal maintenance and remodelling. Prolonged use of a formulation containing these peptides in a split-face clinical study led to significantly improved measures of crow's feet and firmness in a mixed population. CONCLUSIONS: This approach to peptide discovery and testing can identify new synthetic matrikines, providing insights into biological mechanisms of tissue homeostasis and repair and new pathways to clinical intervention.
背景：细胞外基质在组织结构和功能中起着至关重要的作用，这些基质的异常重塑是许多与年龄相关疾病的标志。在皮肤中，真皮胶原的丧失和弹性纤维成分的紊乱是光老化的关键特征。尽管一些小的基质衍生肽在老化皮肤中的应用已被证明可以有益地影响体外细胞行为，并且在体内影响分子结构和临床外观，但新肽的发现缺乏指导假说。 目的：使用蛋白酶切割位点预测，识别对皮肤成分和结构具有有益作用的新型潜在基质衍生肽。 方法：在这里，我们提出了一种从计算（肽切割预测）到体外（培养的人真皮成纤维细胞的蛋白质组学和转录组学活性测试）再到体内（短期贴片测试和长期分面临床研究）的发现管道，该管道能够识别和表征具有不同活性的肽。 结果：使用该管道，我们表明培养的成纤维细胞对所有应用的肽都有反应，但它们的相关生物活性是序列依赖性的。基于生物活性、毒性和蛋白质来源，我们进一步表征了两种新型肽 GPKG（甘氨酸-脯氨酸-赖氨酸-甘氨酸）和 LSVD（亮氨酸-丝氨酸-缬氨酸-天冬氨酸）的组合，它们在体外作用以增强基质组织和细胞增殖基因的转录，在体内（在短期贴片测试中）促进与上皮和真皮维持和重塑相关的过程。在一项为期 6 个月的分面临床研究中，长时间使用含有这些肽的制剂可显著改善混合人群鱼尾纹和紧致度的测量结果。 结论：这种肽发现和测试的方法可以识别新的合成基质衍生肽，为组织稳态和修复的生物学机制以及临床干预的新途径提供了见解。
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