Berning Manuel, Prätzel-Wunder Silke, Bickenbach Jackie R, Boukamp Petra
1 Department of Genetics of Skin Carcinogenesis, German Cancer Research Center (DKFZ) , Heidelberg, Germany .
2 Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa , Iowa City, Iowa.
Tissue Eng Part C Methods. 2015 Sep;21(9):958-70. doi: 10.1089/ten.TEC.2014.0698. Epub 2015 May 7.
Three-dimensional in vitro skin and skin cancer models help to dissect epidermal-dermal and tumor-stroma interactions. In the model presented here, normal human dermal fibroblasts isolated from adult skin self-assembled into dermal equivalents with their specific fibroblast-derived matrix (fdmDE) over 4 weeks. The fdmDE represented a complex human extracellular matrix that was stabilized by its own heterogeneous collagen fiber meshwork, largely resembling a human dermal in vivo architecture. Complemented with normal human epidermal keratinocytes, the skin equivalent (fdmSE) thereof favored the establishment of a well-stratified and differentiated epidermis and importantly allowed epidermal regeneration in vitro for at least 24 weeks. Moreover, the fdmDE could be used to study the features of cutaneous skin cancer. Complementing fdmDE with HaCaT cells in different stages of malignancy or tumor-derived cutaneous squamous cell carcinoma cell lines, the resulting skin cancer equivalents (fdmSCEs) recapitulated the respective degree of tumorigenicity. In addition, the fdmSCE invasion phenotypes correlated with their individual degree of tissue organization, disturbance in basement membrane organization, and presence of matrix metalloproteinases. Together, fdmDE-based models are well suited for long-term regeneration of normal human epidermis and, as they recapitulate tumor-specific growth, differentiation, and invasion profiles of cutaneous skin cancer cells, also provide an excellent human in vitro skin cancer model.
三维体外皮肤和皮肤癌模型有助于剖析表皮-真皮和肿瘤-基质相互作用。在此呈现的模型中，从成人皮肤分离出的正常人真皮成纤维细胞在4周内与它们特定的成纤维细胞衍生基质（fdmDE）自组装成真皮等效物。fdmDE代表一种复杂的人细胞外基质，由其自身的异质胶原纤维网络稳定，在很大程度上类似于体内的人真皮结构。用正常人表皮角质形成细胞进行补充后，其皮肤等效物（fdmSE）有利于建立分层良好且分化的表皮，重要的是允许在体外进行至少24周的表皮再生。此外，fdmDE可用于研究皮肤癌的特征。用处于不同恶性阶段的HaCaT细胞或肿瘤来源的皮肤鳞状细胞癌细胞系补充fdmDE，所得到的皮肤癌等效物（fdmSCE）概括了各自的致瘤程度。此外，fdmSCE的侵袭表型与其各自的组织化程度、基底膜组织紊乱以及基质金属蛋白酶的存在相关。总之，基于fdmDE的模型非常适合正常人表皮的长期再生，并且由于它们概括了皮肤癌细胞的肿瘤特异性生长、分化和侵袭特征，也提供了一个出色的人皮肤癌体外模型。
