Varani J, Perone P, Griffiths C E, Inman D R, Fligiel S E, Voorhees J J
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
J Clin Invest. 1994 Nov;94(5):1747-56. doi: 10.1172/JCI117522.
Adult human skin from a sun-protected site (hip) and from a sun-exposed site (forearm) was maintained in organ culture for 12 d in the presence of a serum-free, growth factor-free basal medium. Cultures were incubated under conditions optimized for keratinocyte growth (i.e., in 0.15 mM extracellular Ca2+) or for fibroblast growth (i.e., in 1.4 mM extracellular Ca2+). Treatment with all-trans retinoic acid (RA) induced histological changes in the organ-cultured skin under both conditions which were similar to the changes seen in intact skin after topical application. These included expansion of the viable portion of the epidermis and activation of cells in the dermis. In sun-damaged skin samples, which were characterized by destruction of normal connective tissue elements and presence of thick, dark-staining elastotic fibers, a zone of healthy connective tissue could be seen immediately below the dermo-epidermal junction. This zone was more prominent in RA-treated organ cultures than in matched controls. Associated with these histological changes was an increase in overall protein and extracellular matrix synthesis. In concomitant studies, it was found that RA treatment enhanced survival and proliferation of adult keratinocytes and adult dermal fibroblasts under both low- and high-Ca2+ conditions. In all of these assays, responses of sun-protected and sun-exposed skin were identical. In contrast, responses of neonatal foreskin to RA were similar to those of adult skin in the presence of low-Ca2+ culture medium, but under conditions of high extracellular Ca2+ RA provided little or no additional stimulus. Together these studies suggest that the ability of RA to enhance repair of sun-damaged skin (documented in previous studies) may reflect its ability to influence the behavior of skin in a manner that is age dependent but independent of sun-exposure status.
将来自防晒部位（臀部）和阳光暴露部位（前臂）的成人皮肤，在无血清、无生长因子的基础培养基中进行器官培养12天。培养物在针对角质形成细胞生长优化的条件下（即细胞外Ca2+浓度为0.15 mM）或针对成纤维细胞生长优化的条件下（即细胞外Ca2+浓度为1.4 mM）孵育。在这两种条件下，全反式维甲酸（RA）处理均诱导了器官培养皮肤的组织学变化，这些变化与局部应用后完整皮肤中所见的变化相似。这些变化包括表皮存活部分的扩展和真皮中细胞的激活。在以正常结缔组织成分破坏和存在粗大、深色弹性纤维为特征的晒伤皮肤样本中，在真皮-表皮交界处下方可立即看到一个健康结缔组织区域。该区域在RA处理的器官培养物中比在匹配的对照中更明显。与这些组织学变化相关的是总体蛋白质和细胞外基质合成的增加。在同期研究中发现，在低钙和高钙条件下，RA处理均能提高成人角质形成细胞和成人真皮成纤维细胞的存活率和增殖率。在所有这些试验中，防晒皮肤和阳光暴露皮肤的反应是相同的。相比之下，新生儿包皮在低钙培养基存在下对RA的反应与成人皮肤相似，但在高细胞外钙条件下，RA几乎没有或没有提供额外的刺激。这些研究共同表明，RA增强晒伤皮肤修复的能力（先前研究已证明）可能反映了其以年龄依赖性但独立于阳光暴露状态的方式影响皮肤行为的能力。
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