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首页> 外文期刊>Aging and Disease >Dyskeratosis Congenita Dermal Fibroblasts are Defective in Supporting the Clonogenic Growth of Epidermal Keratinocytes
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Dyskeratosis Congenita Dermal Fibroblasts are Defective in Supporting the Clonogenic Growth of Epidermal Keratinocytes

机译：角化不全先天性皮肤成纤维细胞在支持表皮角质形成细胞克隆生长方面存在缺陷。

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Telomere shortening is associated with cellular senescence and aging. Dyskeratosis congenita (DC) is a premature aging syndrome caused by mutations in genes for telomerase components or telomere proteins. DC patients have very short telomeres and exhibit aging-associated pathologies including epidermal abnormalities and bone marrow failure. Here, we show that DC skin fibroblasts are defective in their ability to support the clonogenic growth of epidermal keratinocytes. Conditioned media transfer experiments demonstrated that this defect was largely due to lack of a factor or factors secreted from the DC fibroblasts. Compared to early passage normal fibroblasts, DC fibroblasts express significantly lower transcript levels of several genes that code for secreted proteins, including Insulin-like Growth Factor 1 (IGF1) and Hepatocyte Growth Factor (HGF). Aged normal fibroblasts with short telomeres also had reduced levels of IGF1 and HGF, similar to early passage DC fibroblasts. Knockdown of IGF1 or HGF in normal fibroblasts caused a reduction in the capacity of conditioned media from these fibroblasts to support keratinocyte clonogenic growth. Surprisingly, reconstitution of telomerase in DC fibroblasts did not significantly increase transcript levels of IGF1 or HGF or substantially increase the ability of the fibroblasts to support keratinocyte growth, indicating that the gene expression defect is not readily reversible. Our results suggest that telomere shortening in dermal fibroblasts leads to reduction in expression of genes such as IGF1 and HGF and that this may cause a defect in supporting normal epidermal proliferation.
机译：端粒缩短与细胞衰老和衰老有关。先天性角化病（DC）是由端粒酶成分或端粒蛋白基因突变引起的早衰综合症。 DC患者的端粒非常短，并且表现出与衰老相关的病理，包括表皮异常和骨髓衰竭。在这里，我们显示DC皮肤成纤维细胞在支持表皮角质形成细胞克隆生长方面的能力存在缺陷。有条件的介质转移实验表明，该缺陷主要是由于缺乏DC成纤维细胞分泌的一个或多个因素。与早期传代的正常成纤维细胞相比，DC成纤维细胞表达几种编码分泌蛋白的基因的转录水平要低得多，这些基因包括胰岛素样生长因子1（IGF1）和肝细胞生长因子（HGF）。具有短端粒的老化正常成纤维细胞也具有降低的IGF1和HGF水平，类似于早期传代的DC成纤维细胞。正常成纤维细胞中IGF1或HGF的敲低导致这些成纤维细胞中条件培养基支持角质形成细胞克隆形成生长的能力降低。出人意料的是，DC成纤维细胞中端粒酶的重组并没有显着增加IGF1或HGF的转录水平，也没有显着提高成纤维细胞支持角质形成细胞生长的能力，表明基因表达缺陷不易逆转。我们的结果表明，真皮成纤维细胞中端粒的缩短导致IGF1和HGF等基因表达的减少，这可能会导致支持正常表皮增殖的缺陷。

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