Efficient Keratinocyte Differentiation Strictly Depends on JNK-Induced Soluble Factors in Fibroblasts
Efficient Keratinocyte Differentiation Strictly Depends on JNK-Induced Soluble Factors in Fibroblasts
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DOI：
10.1038/jid.2013.535
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发表时间：
2014-05-01
影响因子：
6.5
通讯作者：
Hartenstein, Bettina
中科院分区：
文献类型：
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作者：
Schumacher, Marion;Schuster, Christian;Hartenstein, Bettina
先前的研究表明，成纤维细胞衍生的和jun依赖的可溶性因子在皮肤伤口愈合过程中对角质细胞的增殖和分化起着至关重要的作用。此外，Jun n -末端激酶（JNKs）、JNK1或JNK2缺乏的小鼠表现出皮肤发育受损和伤口愈合延迟。为了解释在这些过程中皮肤JNK在角质形成细胞行为中的作用，我们使用了一种结合原代人角质形成细胞和小鼠成纤维细胞的异种共培养模型。虽然共培养的JNK1/JNK2缺陷成纤维细胞不会影响角质形成细胞的增殖，但对分化的角质形成细胞转录组的时间监测显示，有效的角质形成细胞分化不仅需要成纤维细胞衍生的可溶性因子的支持，而且还严重依赖于这些细胞中的JNK1和JNK2信号传导。此外，我们发现，在共培养条件下，JNK缺失后，编码分泌蛋白的成纤维细胞转录本库严重紊乱。最后，我们的数据表明，有效的角化细胞终末分化需要jnk依赖性和成纤维细胞衍生的可溶性因子的持续存在。综上所述，我们的研究结果表明，在伤口愈合过程中，间充质JNK在真皮成纤维细胞和表皮角质形成细胞之间的旁分泌串音中起关键作用。
Previous studies demonstrated that fibroblast-derived and JUN-dependent soluble factors have a crucial role on keratinocyte proliferation and differentiation during cutaneous wound healing. Furthermore, mice with a deficiency in Jun N-terminal kinases (JNKs), JNK1 or JNK2, showed impaired skin development and delayed wound closure. To decipher the role of dermal JNK in keratinocyte behavior during these processes, we used a heterologous coculture model combining primary human keratinocytes and murine fibroblasts. Although cocultured JNK1/JNK2-deficient fibroblasts did not affect keratinocyte proliferation, temporal monitoring of the transcriptome of differentiating keratinocytes revealed that efficient keratinocyte differentiation not only requires the support by fibroblast-derived soluble factors, but is also critically dependent on JNK1 and JNK2 signaling in these cells. Moreover, we showed that the repertoire of fibroblast transcripts encoding secreted proteins is severely disarranged upon loss of JNK under the coculture conditions applied. Finally, our data demonstrate that efficient keratinocyte terminal differentiation requires constant presence of JNK-dependent and fibroblast-derived soluble factors. Taken together, our results imply that mesenchymal JNK has a pivotal role in the paracrine cross talk between dermal fibroblasts and epidermal keratinocytes during wound healing.