Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-β1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt.
Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-β1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt.
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DOI：
10.3390/ijms18112431
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发表时间：
2017-11-16
影响因子：
5.6
通讯作者：
Alcaraz J
中科院分区：
文献类型：
--
作者：
Giménez A;Duch P;Puig M;Gabasa M;Xaubet A;Alcaraz J
特发性肺纤维化(IPF)是一种侵袭性疾病，在这种疾病中，正常的肺实质被含有大量活化的成纤维细胞和I型胶原的僵硬的功能障碍疤痕所取代。我们研究了在正常和纤维化条件下，由基质硬化和转化生长因子-β1提供的机械力化学促纤维化微环境是如何在转录调控胶原动态平衡中协同作用的。为此，我们将IPF患者或对照供体的成纤维细胞培养在弹性可调的水凝胶上，包括3D-I型胶原凝胶和2D聚丙烯酰胺(PAA)凝胶。我们发现，转化生长因子-Akt 1持续增加COL1A1，同时降低表现为纤维化前或纤维样僵硬的水凝胶中的MMP1mRNA水平，同时伴随着β/Akt通路的增强，而FAK的耗竭足以消除这些影响。我们还证明了基质硬化和转化生长因子-β1之间的协同作用，即COL1A1阳性而MMP1阴性。值得注意的是，转化生长因子-β1单独或与基质硬化协同诱导的COL1A1表达上调在成纤维细胞中高于对照成纤维细胞，与前者中较大的FAK和AKT活性有关。这些发现为基质硬化和转化生长因子-β-1如何协同诱导间质纤维化中I型胶原过度沉积提供了新的见解，并支持FAK/AKT通路在这一协同作用中的重要作用。
Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-β1 cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide (PAA) gels. We found that TGF-β1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and TGF-β1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-β1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells. These findings provide new insights on how matrix stiffening and TGF-β1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation.
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影响因子：
4
作者：
Cutroneo, KR
通讯作者：
Cutroneo, KR
层粘连蛋白和仿生细胞外弹性增强了乳腺上皮的功能分化。
影响因子：
11.4
作者：
Alcaraz, Jordi;Xu, Ren;Mori, Hidetoshi;Nelson, Celeste M.;Mroue, Rana;Spencer, Virginia A.;Brownfield, Doug;Radisky, Derek C.;Bustamante, Carlos;Bissell, Mina J.
通讯作者：
Bissell, Mina J.
DOI：
10.1164/ajrccm.162.4.9912011
发表时间：
2000-10-01
影响因子：
24.7
作者：
Ebihara, T;Venkatesan, N;Ludwig, MS
通讯作者：
Ludwig, MS
影响因子：
4.8
作者：
Chen, HC;Appeddu, PA;Guan, JL
通讯作者：
Guan, JL
DOI：
10.1016/j.biocel.2008.02.012
发表时间：
2008-01-01
影响因子：
4
作者：
Andersson-Sjoland, Annika;de Alba, Carolina Garcia;Selman, Moises
通讯作者：
Selman, Moises