Reversible modulation of myofibroblast differentiation in adipose-derived mesenchymal stem cells.
Reversible modulation of myofibroblast differentiation in adipose-derived mesenchymal stem cells.
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DOI：
10.1371/journal.pone.0086865
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Schwarzbauer JE
中科院分区：
文献类型：
--
作者：
Desai VD;Hsia HC;Schwarzbauer JE
肌成纤维细胞（存款丰富的细胞外基质（ECM）的高度收缩性细胞）的不受调节的活性导致纤维化。为了研究肌成纤维细胞活性的调节，我们使用了在再生医学中具有很大潜力的人脂肪间充质干细胞（ADSC）。我们发现用TGF-β处理的ADSC发展成肌纤维母细胞表型，其中α-平滑肌肌动蛋白（α-SMA）（肌成纤维细胞标志物）和ECM蛋白I型胶原和纤连蛋白增加。与此相反，bFGF治疗有相反的效果。bFGF分化的ADSC表现出α-SMA表达、胶原I和纤连蛋白的显著下调，以及局灶性粘连和应力纤维的丢失。在功能上，bFGF分化的ADSC迁移性明显增强，这与抗粘附ECM蛋白生腱蛋白-C和促迁移细胞骨架蛋白波形蛋白的上调相关。另一方面，TGF-β分化的ADSC比bFGF分化的细胞显著更收缩。有趣的是，细胞完全逆转其形态，标志物的表达，信号传导途径，和收缩性与迁移的配置文件时，从一种生长因子的文化切换到其他，表明肌成纤维细胞分化过程不是终端。细胞分化与TGF-β下游的Smad 2和bFGF下游的ERK/MAP激酶的激活有关。TGF-β诱导的成肌纤维细胞表型的可逆性部分取决于bFGF诱导的ERK/MAP激酶信号传导。这些发现表明，ADSC分化成肌成纤维细胞和再分化成纤维细胞样细胞可以用生长因子操纵，这可能对开发新的治疗策略以降低纤维化风险具有意义。
Unregulated activity of myofibroblasts, highly contractile cells that deposit abundant extracellular matrix (ECM), leads to fibrosis. To study the modulation of myofibroblast activity, we used human adipose-derived mesenchymal stem cells (ADSCs), which have much potential in regenerative medicine. We found that ADSCs treated with TGF-β developed a myofibroblastic phenotype with increases in α-smooth muscle actin (α-SMA), a myofibroblast marker, and ECM proteins type I collagen and fibronectin. In contrast, treatment with bFGF had the opposite effect. bFGF-differentiated ADSCs showed marked down-regulation of α-SMA expression, collagen I, and fibronectin, and loss of focal adhesions and stress fibers. Functionally, bFGF-differentiated ADSCs were significantly more migratory, which correlated with up-regulation of tenascin-C, an anti-adhesive ECM protein, and vimentin, a pro-migratory cytoskeletal protein. On the other hand, TGF-β-differentiated ADSCs were significantly more contractile than bFGF-differentiated cells. Interestingly, cells completely reversed their morphologies, marker expression, signaling pathways, and contractility versus migratory profiles when switched from culture with one growth factor to the other, demonstrating that the myofibroblast differentiation process is not terminal. Cell differentiation was associated with activation of Smad2 downstream of TGF-β and of ERK/MAP kinase downstream of bFGF. Reversibility of the TGF-β-induced myofibroblastic phenotype depends, in part, on bFGF-induced ERK/MAP kinase signaling. These findings show that ADSC differentiation into myofibroblasts and re-differentiation into fibroblast-like cells can be manipulated with growth factors, which may have implications in the development of novel therapeutic strategies to reduce the risk of fibrosis.
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影响因子：
14
作者：
Khouw, IMSL;van Wachem, PB;van Luyn, MJA
通讯作者：
van Luyn, MJA
影响因子：
5.2
作者：
Jeon, Eun Su;Moon, Hyun Jung;Kim, Jae Ho
通讯作者：
Kim, Jae Ho
影响因子：
4.8
作者：
Kim, Dong-Hwee;Wirtz, Denis
通讯作者：
Wirtz, Denis
影响因子：
4.8
作者：
Cushing, Melinda C.;Mariner, Peter D.;Liao, Jo-Tsu;Sims, Evan A.;Anseth, Kristi S.
通讯作者：
Anseth, Kristi S.
影响因子：
4.8
作者：
ALESSI, DR;CUENDA, A;SALTIEL, AR
通讯作者：
SALTIEL, AR