Haake A R, Cooklis M
Department of Dermatology, The University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
Exp Cell Res. 1997 Feb 25;231(1):83-95. doi: 10.1006/excr.1996.3441.
The program of epidermal morphogenesis and differentiation changes dramatically during development of human fetal skin. Keratinocytes derived from fetal basal cells at early stages undergo only an incomplete keratinization and are eventually replaced by newly formed fetal keratinocytes that complete the terminal differentiation program and form the first stratum granulosum and stratum corneum. Once established, this program is reiterated throughout life, as the epidermis continually renews. To test the developmental potential of early fetal keratinocytes, we have cultured them in the physiologic skin equivalent (SE) system in the presence of varied retinoic acid (RA) concentrations and have compared them to neonatal keratinocytes cultured under the same conditions. The responses of fetal and neonatal SEs have been characterized by analysis of epidermal morphology, the presence and distribution of RA-responsive and differentiation-specific keratins and filaggrin, proliferation, and apoptosis. Our study shows that fetal basal keratinocytes already are programmed to form the granular layer and incomplete stratum corneum, even when isolated from a stage prior to formation of these layers. Fetal keratinocytes respond differently than neonatal keratinocytes to RA in terms of modulation of both epidermal morphology and expression of differentiation markers. Modulation of RA-responsive K1 and K19 occurs in both fetal SE and neonatal SE but the fetal keratinocyte responds at lower RA concentrations in the medium. In contrast, fetal keratinocytes appear to be less responsive than neonatal keratinocytes in terms of filaggrin expression and stratum corneum formation. These differences in the differentiation and RA response in vitro may be related to inherent stage-specific differences between fetal and neonatal keratinocytes in RA-signaling pathways including expression of the retinoic acid receptor, RARbeta. Furthermore, high rates of apoptosis in the fetal SE suggest that apoptosis is the default pathway that is taken in the absence of complete keratinocyte differentiation.
在人类胎儿皮肤发育过程中，表皮形态发生和分化程序会发生显著变化。早期源自胎儿基底细胞的角质形成细胞仅经历不完全角化，最终会被新形成的胎儿角质形成细胞取代，这些新细胞完成终末分化程序并形成第一层颗粒层和角质层。一旦确立，该程序会在整个生命过程中反复进行，因为表皮会持续更新。为了测试早期胎儿角质形成细胞的发育潜能，我们在不同视黄酸（RA）浓度存在的情况下，将它们培养在生理性皮肤等效物（SE）系统中，并将其与在相同条件下培养的新生儿角质形成细胞进行比较。通过分析表皮形态、RA反应性和分化特异性角蛋白及丝聚合蛋白的存在与分布、增殖和凋亡情况，对胎儿和新生儿SE的反应进行了表征。我们的研究表明，即使从这些层形成之前的阶段分离出来，胎儿基底角质形成细胞也已被编程形成颗粒层和不完全角质层。在表皮形态调节和分化标志物表达方面，胎儿角质形成细胞对RA的反应与新生儿角质形成细胞不同。RA反应性K1和K19在胎儿SE和新生儿SE中均发生调节，但胎儿角质形成细胞在培养基中较低的RA浓度下就会产生反应。相比之下，在丝聚合蛋白表达和角质层形成方面，胎儿角质形成细胞似乎比新生儿角质形成细胞反应性更低。体外分化和RA反应的这些差异可能与胎儿和新生儿角质形成细胞在RA信号通路中的固有阶段特异性差异有关，包括视黄酸受体RARβ的表达。此外，胎儿SE中高凋亡率表明，凋亡是在角质形成细胞未完全分化时的默认途径。
