Inhibition of apoptosis signal-regulating kinase 1 alters the wound epidermis and enhances auricular cartilage regeneration.
Inhibition of apoptosis signal-regulating kinase 1 alters the wound epidermis and enhances auricular cartilage regeneration.
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DOI：
10.1371/journal.pone.0185803
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Freeman TA
中科院分区：
文献类型：
--
作者：
Zhang QS;Kurpad DS;Mahoney MG;Steinbeck MJ;Freeman TA
为什么再生不会发生在哺乳动物身上仍然是一个谜。在低等脊椎动物中，肢体的表型再生由伤口表皮指导，伤口表皮控制芽基的形成以促进附肢的再生。在此，我们报告了敲除（KO）或抑制凋亡信号调节激酶-1（ASK 1），也称为丝裂原活化蛋白激酶5（MAP 3 K5），在小鼠全层耳穿孔后，抑制伤口表皮内的角质形成细胞活化并促进耳软骨再生。组织学分析显示，ASK 1 KO耳显示与胚基形成、孔闭合和耳软骨再生相关的蛋白标记物增强。在打孔后7天，KO中的伤口表皮形态明显不同，显示出具有圆形细胞形态的增厚的角质层和颗粒细胞层的减少以及细丝聚集蛋白的表达降低。此外，细胞角蛋白6在棘层和颗粒层中表达。局部应用ASK 1抑制剂（NQDI-1）、上游ASK 1激活剂、钙激活丝裂原激酶2（KN 93）或下游靶点c-Jun N-末端激酶（SP 600125）也可增强再生;而抑制另一下游靶点p38 α/β亚型（SB 203580）则无影响。本研究结果表明，ASK 1抑制角质形成细胞和胚基细胞活化，导致耳朵再生。
Why regeneration does not occur in mammals remains elusive. In lower vertebrates, epimorphic regeneration of the limb is directed by the wound epidermis, which controls blastema formation to promote regrowth of the appendage. Herein, we report that knockout (KO) or inhibition of Apoptosis Signal-regulated Kinase-1 (ASK1), also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), after full thickness ear punch in mice prolongs keratinocyte activation within the wound epidermis and promotes regeneration of auricular cartilage. Histological analysis showed the ASK1 KO ears displayed enhanced protein markers associated with blastema formation, hole closure and regeneration of auricular cartilage. At seven days after punch, the wound epidermis morphology was markedly different in the KO, showing a thickened stratum corneum with rounded cell morphology and a reduction of both the granular cell layer and decreased expression of filament aggregating protein. In addition, cytokeratin 6 was expressed in the stratum spinosum and granulosum. Topical application of inhibitors of ASK1 (NQDI-1), the upstream ASK1 activator, calcium activated mitogen kinase 2 (KN93), or the downstream target, c-Jun N-terminal kinase (SP600125) also resulted in enhanced regeneration; whereas inhibition of the other downstream target, the p38 α/β isoforms, (SB203580) had no effect. The results of this investigation indicate ASK1 inhibition prolongs keratinocyte and blastemal cell activation leading to ear regeneration.
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影响因子：
6.5
作者：
Schumacher, Marion;Schuster, Christian;Hartenstein, Bettina
通讯作者：
Hartenstein, Bettina
DOI：
10.1073/pnas.89.13.6162
发表时间：
1992-07-01
影响因子：
11.1
作者：
NIGAM, SK;RODRIGUEZBOULAN, E;SILVER, RB
通讯作者：
SILVER, RB
影响因子：
23.9
作者：
Shyh-Chang, Ng;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
2.6
作者：
Deoliveira D;Jiao Y;Ross JR;Corbin K;Xiao Q;Toncheva G;Anderson-Evans C;Yoshizumi TT;Chen BJ;Chao NJ
通讯作者：
Chao NJ
影响因子：
3.2
作者：
Bikle DD;Xie Z;Tu CL
通讯作者：
Tu CL