MicroRNA-7 inhibition rescues age-associated loss of epidermal growth factor receptor and hyaluronan-dependent differentiation in fibroblasts.
MicroRNA-7 inhibition rescues age-associated loss of epidermal growth factor receptor and hyaluronan-dependent differentiation in fibroblasts.
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DOI：
10.1111/acel.12167
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发表时间：
2014-04
期刊：
影响因子：
7.8
通讯作者：
Steadman R
中科院分区：
文献类型：
--
作者：
Midgley AC;Bowen T;Phillips AO;Steadman R
成纤维细胞分化中的年龄相关缺陷先前被证明与透明质酸合成酶2 （HAS2）和表皮生长因子受体（EGFR）功能受损有关，两者都是正常成纤维细胞功能所必需的。在成纤维细胞中，转化生长因子-β1 （TGF-β1）依赖的表型激活使用两种不同但协同作用的途径，包括TGF-β受体(TGF-β r)/Smad2激活和ha介导的CD44-EGFR共定位，并通过细胞外信号调节激酶1/2 （ERK1/2）发出信号。ha介导的CD44-EGFR通路通过EGFR表达的丧失和CD44在细胞膜上的运动减少而受到体外衰老的损害。在这里，我们还通过研究miRNA-7 （miR-7）对ha介导的egfr信号通路的调节，研究了microRNAs （miRNAs）在年龄相关的分化丧失中的作用。发现miR-7的转录在衰老细胞中上调。在年轻细胞中，年龄相关的分化丧失可以通过转染pre-miR-7来模拟，而在衰老细胞中，可以通过转染靶向miR-7的锁定核酸（LNA）来逆转。此外，miR-7被发现参与CD44膜运动的调节，在miR-7上调的情况下，CD44膜运动下调，并通过miR-7抑制或HAS2过表达部分恢复。细胞膜中CD44的动力学改变表明miR-7在调节ha依赖性CD44/EGFR通路中的进一步作用。我们解释了这种由miR-7上调引起的年龄相关功能后果的新机制，并证明它是可逆的；强调miR-7是恢复老年人慢性伤口愈合能力的潜在靶点。
Age-related defects in fibroblast differentiation were previously shown to be associated with impaired hyaluronan synthase 2 (HAS2) and epidermal growth factor receptor (EGFR) function, with both required for normal fibroblast functionality. In fibroblasts, transforming growth factor-beta 1 (TGF-β1)-dependent phenotypic activation uses two distinct but co-operating pathways that involve TGF-β receptor (TGF-βR)/Smad2 activation and HA-mediated CD44-EGFR co-localization and signalling through extracellular signal-regulated kinase 1/2 (ERK1/2). The HA-mediated CD44-EGFR pathway was found to be compromised with in vitro aging, through loss of EGFR expression and a reduced movement of CD44 throughout the cellular membrane. Here, we also investigate the involvement of microRNAs (miRNAs) in age-related loss of differentiation, through investigation of miRNA-7 (miR-7) regulation of the HA-mediated EGFR-signalling pathway. The transcription of miR-7 was found to be upregulated in aged cells. In young cells, age-related loss of differentiation could be mimicked through transfection of pre-miR-7, and in aged cells, could be reversed through transfection of locked nucleic acids (LNA) targeting miR-7. Additionally, miR-7 was found to be involved in the regulation of CD44 membrane motility, which was downregulated in instances of miR-7 upregulation, and partially restorable through either miR-7 inhibition or HAS2 overexpression. The altered dynamics of CD44 in the cell membrane demonstrated a further action of miR-7 in regulating the HA-dependent CD44/EGFR pathway. We explain this novel mechanism of age-associated functional consequence due to miR-7 upregulation and demonstrate that it is reversible; highlighting miR-7 as a potential target for restoring the healing capabilities in chronic wounds in the elderly.
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影响因子：
4.8
作者：
Ito, T;Williams, JD;Phillips, AO
通讯作者：
Phillips, AO
影响因子：
4.8
作者：
Midgley, Adam C.;Rogers, Mathew;Steadman, Robert
通讯作者：
Steadman, Robert
影响因子：
4.8
作者：
Shiraha, H;Gupta, K;Wells, A
通讯作者：
Wells, A
影响因子：
4.8
作者：
Webster, Rebecca J.;Giles, Keith M.;Leedman, Peter J.
通讯作者：
Leedman, Peter J.
影响因子：
11.2
作者：
Kefas, Benjamin;Godlewski, Jakub;Purow, Benjamin
通讯作者：
Purow, Benjamin