Rendl Michael, Lewis Lisa, Fuchs Elaine
Howard Hughes Medical Institute, The Rockefeller University, New York, New York, United States of America.
PLoS Biol. 2005 Nov;3(11):e331. doi: 10.1371/journal.pbio.0030331. Epub 2005 Sep 20.
De novo hair follicle formation in embryonic skin and new hair growth in adult skin are initiated when specialized mesenchymal dermal papilla (DP) cells send cues to multipotent epithelial stem cells. Subsequently, DP cells are enveloped by epithelial stem cell progeny and other cell types to form a niche orchestrating hair growth. Understanding the general biological principles that govern the mesenchymal-epithelial interactions within the DP niche, however, has been hampered so far by the lack of systematic approaches to dissect the complete molecular make-up of this complex tissue. Here, we take a novel multicolor labeling approach, using cell type-specific transgenic expression of red and green fluorescent proteins in combination with immunolabeling of specific antigens, to isolate pure populations of DP and four of its surrounding cell types: dermal fibroblasts, melanocytes, and two different populations of epithelial progenitors (matrix and outer root sheath cells). By defining their transcriptional profiles, we develop molecular signatures characteristic for the DP and its niche. Validating the functional importance of these signatures is a group of genes linked to hair disorders that have been largely unexplored. Additionally, the DP signature reveals novel signaling and transcription regulators that distinguish them from other cell types. The mesenchymal-epithelial signatures include key factors previously implicated in ectodermal-neural fate determination, as well as a myriad of regulators of bone morphogenetic protein signaling. These findings establish a foundation for future functional analyses of the roles of these genes in hair development. Overall, our strategy illustrates how knowledge of the genes uniquely expressed by each cell type residing in a complex niche can reveal important new insights into the biology of the tissue and its associated disease states.
当特化的间充质真皮乳头（DP）细胞向多能上皮干细胞发送信号时，胚胎皮肤中会启动从头毛囊形成，成体皮肤中会开始新的毛发生长。随后，DP细胞被上皮干细胞后代和其他细胞类型包裹，形成一个协调毛发生长的生态位。然而，由于缺乏系统的方法来剖析这个复杂组织的完整分子组成，迄今为止，了解DP生态位内间充质-上皮相互作用的一般生物学原理受到了阻碍。在这里，我们采用了一种新颖的多色标记方法，利用红色和绿色荧光蛋白的细胞类型特异性转基因表达，并结合特定抗原的免疫标记，来分离DP及其四种周围细胞类型的纯群体：真皮成纤维细胞、黑素细胞以及两种不同的上皮祖细胞群体（基质细胞和外根鞘细胞）。通过定义它们的转录谱，我们开发了DP及其生态位特有的分子特征。验证这些特征功能重要性的是一组与毛发疾病相关但在很大程度上未被探索的基因。此外，DP特征揭示了将它们与其他细胞类型区分开来的新信号传导和转录调节因子。间充质-上皮特征包括先前与外胚层-神经命运决定有关的关键因子，以及骨形态发生蛋白信号传导的众多调节因子。这些发现为未来对这些基因在毛发发育中的作用进行功能分析奠定了基础。总体而言，我们的策略说明了了解存在于复杂生态位中的每种细胞类型独特表达的基因如何能够揭示对该组织生物学及其相关疾病状态的重要新见解。
