Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness due to preferential loss of EGF receptors
Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness due to preferential loss of EGF receptors
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DOI：
10.1074/jbc.m000008200
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发表时间：
2000-06-23
影响因子：
4.8
通讯作者：
Wells, A
中科院分区：
文献类型：
--
作者：
Shiraha, H;Gupta, K;Wells, A
在老年人中，伤口愈合受到损害，部分原因是成纤维细胞对细胞外信号的反应性降低。然而，这种现象背后的细胞机制尚不清楚。正如之前报道的那样，老化的皮肤成纤维细胞的剩余复制能力降低，表现出表皮生长因子（EGF）诱导的细胞迁移和细胞增殖能力下降。因此，当细胞接近衰老时，无论是体内还是体外，EGF的反应性都会优先丧失。为了定义限速信号事件，我们发现，尽管效应分子水平不变，但在接近衰老的细胞中，两种不同的EGF受体(EGFR)-细胞迁移信号通路（磷脂酶- c γ）和/或有丝分裂发生（细胞外信号/调节的有丝分裂原激活激酶）的活性却降低了。衰老细胞EGFR水平下降，但胰岛素受体和转铁蛋白受体水平相对不变。随着年龄的增长，EGFR、mRNA水平和新转录本的产生都有所下降，这表明EGFR的优先损失是由于产量减少，这远远抵消了配体诱导的受体损失的减少。由于这些数据表明EGF的减少是有速率限制的，因此通过电穿孔EGFR cDNA在接近衰老的细胞中建立了较高水平的EGFR。这些细胞表现出更高水平的EGFR，并恢复了egf诱导的迁移和增殖反应。因此，衰老真皮成纤维细胞的EGF反应性缺陷是继发于EGFR信息转录减少。我们的实验模型表明，EGFR基因递送可能是未来治疗受损伤口愈合的有效方法。
Wound healing is compromised in aging adults in part due to decreased responsiveness of fibroblasts to extracellular signals. However, the cellular mechanisms underlying this phenomenon are not known. Aged dermal fibroblasts with reduced remaining replicative capacities demonstrated decreased epidermal growth factor (EGF)-induced cell migrative and cell proliferative capacities, as reported previously. Thus, as cells approach senescence, programmed in vivo or in vitro, EGF responsiveness is preferentially lost. To define the rate-limiting signaling event, we found that the activity of two different EGF receptor (EGFR)-signaling pathways to cell migration (phospholipase-C gamma) and/or mitogenesis (extracellular signal/regulated-mitogen-activated kinases) were decreased in near senescent cells despite unchanged levels of effector molecules. Aged cells presented decreased levels of EGFR, although insulin receptor and transferrin receptor levels were relatively unchanged. EGFR, mRNA levels and production of new transcripts decreased during aging, suggesting that this preferential loss of EGFR was due to diminished production, which more than counteracts the reduced ligand-induced receptor loss. Since these data suggested that the decrement in EGF was rate-limiting, higher levels of EGFR were established in near senescent cells by electroporation of EGFR cDNA. These cells presented higher levels of EGFR and recovered their EGF-induced migration and proliferation responsiveness. Thus, the defect in EGF responsiveness of aged dermal fibroblasts is secondary to reduced EGFR message transcription. Our experimental model suggests that EGFR gene delivery might be an effective future therapy for compromised wound healing.