JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.
JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.
复制标题
DOI：
10.1126/scitranslmed.abb3312
复制
发表时间：
2021-09
影响因子：
17.1
通讯作者：
Longaker MT
中科院分区：
文献类型：
--
作者：
Griffin MF;Borrelli MR;Garcia JT;Januszyk M;King M;Lerbs T;Cui L;Moore AL;Shen AH;Mascharak S;Diaz Deleon NM;Adem S;Taylor WL;desJardins-Park HE;Gastou M;Patel RA;Duoto BA;Sokol J;Wei Y;Foster D;Chen K;Wan DC;Gurtner GC;Lorenz HP;Chang HY;Wernig G;Longaker MT
病理性皮肤瘢痕形成是一个巨大的经济和医疗负担。不幸的是，瘢痕形成的分子机制仍有待阐明。我们使用了肥厚性瘢痕（HTS）小鼠模型，在该模型中，Jun在α-平滑肌或i型胶原表达细胞中整体或特异性过表达，导致皮肤成纤维细胞在皮肤损伤后过度沉积细胞外基质。Jun过表达通过调节伤口内不同的成纤维细胞亚群、增加网状成纤维细胞数量和减少脂肪成纤维细胞来触发皮肤纤维化。对人类疤痕的分析进一步表明，JUN在广泛的疤痕中高度表达，包括HTS和瘢痕疙瘩。crispr - cas9介导的人HTS成纤维细胞JUN缺失，结合对人和小鼠HTS成纤维细胞的表观基因组学和转录组学分析显示，JUN通过调节CD36启动纤维化。用丹酚酸B阻断CD36或敲除CD36模型可抵消jun介导的人成纤维细胞和小鼠伤口纤维化的作用。总之，JUN是病理性皮肤瘢痕形成的关键调节因子，靶向其下游效应物CD36可能是一种治疗瘢痕形成的策略。
Pathologic skin scarring presents a vast economic and medical burden. Unfortunately, the molecular mechanisms underlying scar formation remain to be elucidated. We used a hypertrophic scarring (HTS) mouse model in which Jun is overexpressed globally or specifically in α-smooth muscle or collagen type I–expressing cells to cause excessive extracellular matrix deposition by skin fibroblasts in the skin after wounding. Jun overexpression triggered dermal fibrosis by modulating distinct fibroblast subpopulations within the wound, enhancing reticular fibroblast numbers, and decreasing lipofibroblasts. Analysis of human scars further revealed that JUN is highly expressed across the wide spectrum of scars, including HTS and keloids. CRISPR-Cas9–mediated JUN deletion in human HTS fibroblasts combined with epigenomic and transcriptomic analysis of both human and mouse HTS fibroblasts revealed that JUN initiates fibrosis by regulating CD36. Blocking CD36 with salvianolic acid B or CD36 knockout model counteracted JUN-mediated fibrosis efficacy in both human fibroblasts and mouse wounds. In summary, JUN is a critical regulator of pathological skin scarring, and targeting its downstream effector CD36 may represent a therapeutic strategy against scarring.
登录
查看更多内容
丹酚酸 B 通过抑制 TGF-β 信号通路减轻实验性肺纤维化
影响因子：
4.6
作者：
Liu Q;Chu H;Ma Y;Wu T;Qian F;Ren X;Tu W;Zhou X;Jin L;Wu W;Wang J
通讯作者：
Wang J
无疤痕胎儿伤口愈合：基础科学评论。
影响因子：
3.6
作者：
Larson BJ;Longaker MT;Lorenz HP
通讯作者：
Lorenz HP
影响因子：
8
作者：
Lerbs, Tristan;Cui, Lu;Wernig, Gerlinde
通讯作者：
Wernig, Gerlinde
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
64.8
作者：
通讯作者：
--