Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds.
Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds.
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DOI：
10.1038/s42003-021-02298-5
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发表时间：
2021-06-18
影响因子：
5.9
通讯作者：
Tomic-Canic M
中科院分区：
文献类型：
--
作者：
Jozic I;Abujamra BA;Elliott MH;Wikramanayake TC;Marjanovic J;Stone RC;Head CR;Pastar I;Kirsner RS;Andreopoulos FM;Musi JP;Tomic-Canic M
虽然受损的角质形成细胞迁移是公认的慢性伤口的标志，但对受损细胞运动的分子机制知之甚少。在这里，我们证明了糖尿病足溃疡（DFU）和静脉性下肢溃疡（VLU）表现出全球失调的细胞骨架组织的基因组比较正常的皮肤和急性伤口。有趣的是，我们发现DFU和VLU表现出ArhGAP 35的下调，ArhGAP 35既作为RhoA的灭活剂又作为糖皮质激素的阻遏物。由于慢性伤口表现出皮质醇和小窝蛋白-1（Cav 1）水平升高，我们假设观察到Cav 1表达的升高可能有助于受损的肌动蛋白-细胞骨架信号传导，表现为异常的角质形成细胞迁移。我们发现Cav 1确实拮抗ArhGAP 35，导致RhoA的激活增加和Cdc 42的激活减少，这可以通过Cav 1破坏来挽救。此外，我们证明了诱导型角质形成细胞特异性Cav 1基因敲除小鼠和MβCD治疗的糖尿病小鼠都表现出加速的伤口闭合。综上所述，我们的研究结果提供了一种以前未报道的机制，Cav 1介导的细胞骨架组织阻止慢性伤口患者的伤口闭合。Jozic等人观察到慢性伤口中细胞骨架成分失调，皮质醇和小窝蛋白-1水平升高。他们还表明，糖尿病小鼠中诱导性角质形成细胞特异性Cav 1敲除或药物诱导的胆固醇破坏导致伤口加速闭合，这表明糖尿病足溃疡的治疗方法。
Although impaired keratinocyte migration is a recognized hallmark of chronic wounds, the molecular mechanisms underpinning impaired cell movement are poorly understood. Here, we demonstrate that both diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) exhibit global deregulation of cytoskeletal organization in genomic comparison to normal skin and acute wounds. Interestingly, we found that DFUs and VLUs exhibited downregulation of ArhGAP35, which serves both as an inactivator of RhoA and as a glucocorticoid repressor. Since chronic wounds exhibit elevated levels of cortisol and caveolin-1 (Cav1), we posited that observed elevation of Cav1 expression may contribute to impaired actin-cytoskeletal signaling, manifesting in aberrant keratinocyte migration. We showed that Cav1 indeed antagonizes ArhGAP35, resulting in increased activation of RhoA and diminished activation of Cdc42, which can be rescued by Cav1 disruption. Furthermore, we demonstrate that both inducible keratinocyte specific Cav1 knockout mice, and MβCD treated diabetic mice, exhibit accelerated wound closure. Taken together, our findings provide a previously unreported mechanism by which Cav1-mediated cytoskeletal organization prevents wound closure in patients with chronic wounds. Jozic et al observe deregulated cytoskeleton components and elevated levels of cortisol and caveolin-1 in chronic wounds. They also show that inducible-keratinocyte specific Cav1 knockout or drug-induced cholesterol disruption in diabetic mice leads to accelerated wound closure suggesting a therapeutic approach for diabetic foot ulcers.
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影响因子：
--
作者：
Carlson, Mark W;Alt-Holland, Addy;Egles, Christophe;Garlick, Jonathan A
通讯作者：
Garlick, Jonathan A
影响因子：
17.1
作者：
Eming SA;Martin P;Tomic-Canic M
通讯作者：
Tomic-Canic M
DOI：
10.1083/jcb.201003086
发表时间：
2010-11-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hayer A;Stoeber M;Ritz D;Engel S;Meyer HH;Helenius A
通讯作者：
Helenius A
影响因子：
82.9
作者：
Bucci, M;Gratton, JP;Sessa, WC
通讯作者：
Sessa, WC
DOI：
10.1073/pnas.0407224102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Bernatchez, PN;Bauer, PM;Sessa, WC
通讯作者：
Sessa, WC