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Characterization of Epithelial Progenitors in Normal Human Palatine Tonsils

机译:正常人Pala扁桃体上皮祖细胞的表征

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摘要

The palatine tonsils are a collection of lymph nodes overlaid by stratified non-keratinized epithelium that invaginates deep into the tissue, forming tonsillar “crypts” where ingested and inhaled pathogens are collected and initiate an immune response followed by transepithelial lymphocyte infiltration. The dynamic nature of this site suggests the existence of primitive cells responsible for the constant tissue repair and regeneration; however, such cells in the tonsils have not been characterized. Human Papillomavirus (HPV)-associated cancer of oropharynx is a global health concern that is on the rise, with HPV16 oncoproteins E6/E7 frequently detected in the epithelium of tonsillar crypts. It is hypothesized that the long-term self-renewing progenitor cells are the target of HPV-induced malignancy, but the lack of a method to specifically study these critical cells has been a barrier to further investigation. In this study, I have developed and optimized the methodology to identify, isolate and quantitate epithelial progenitors from human palatine tonsil. I show that tonsillar progenitors that form colonies in vitro in 2D colony assays and differentiate into multilayered epithelial tissues in a 3D culture system are CD44+NGFR+ and present in both surface and crypt regions. Transcriptome analysis indicates a high similarity between CD44+NGFR+ cells in both regions, although those isolated from the crypt contained a higher proportion of the most primitive (holo)clonogenic cells. The method was then applied to study effects of HPV infection on purified CD44+NGFR+ cells from both regions. Lentiviral transduction of CD44+NGFR+ cells with HPV16 E6/E7 oncogenes prolonged their growth in 2D cultures and caused aberrant differentiation in 3D cultures. Interestingly, in the presence of the normal cells, the E6/E7-transduced cells proliferated more slowly in 2D cultures and formed uniquely heterogeneous epithelial structures displaying varying degrees of perturbation in 3D cultures suggesting possible inhibitory effects of the cocultured normal cells. The system developed and presented in this thesis allows for a targeted approach to study a specific subset of epithelial cells purified from the tonsillar crypts and their response to E6/E7 infection, setting the stage for addressing many unanswered questions pertaining to the early stages of tonsillar oncogenesis.
机译:tons扁桃体是淋巴结的集合,被分层的非角化上皮覆盖,深入到组织中,形成扁桃体“隐窝”,收集并吸入病原体并开始免疫反应,然后经上皮淋巴细胞浸润。该位点的动态性质表明存在原始细胞,负责恒定的组织修复和再生。然而,扁桃体中的这种细胞尚未被表征。人类乳头瘤病毒(HPV)相关的口咽癌正在引起全球健康关注,在扁桃体隐窝的上皮中经常发现HPV16癌蛋白E6 / E7。假设长期自我更新的祖细胞是HPV诱导的恶性肿瘤的靶标,但是缺乏专门研究这些关键细胞的方法一直是进一步研究的障碍。在这项研究中,我开发并优化了从人identify扁桃体中鉴定,分离和定量上皮祖细胞的方法。我表明在2D菌落测定中在体外形成菌落并在3D培养系统中分化为多层上皮组织的扁桃体祖细胞是CD44 + NGFR +,并且存在于表面和隐窝区域。转录组分析表明,在两个区域中,CD44 + NGFR +细胞之间具有高度相似性,尽管从隐窝中分离出的CD44 + NGFR +细胞中有更多比例的最原始(完整)克隆细胞。然后将该方法应用于研究HPV感染对来自两个区域的纯化CD44 + NGFR +细胞的影响。 HPV16 E6 / E7癌基因对CD44 + NGFR +细胞的慢病毒转导延长了它们在2D培养物中的生长,并导致3D培养物中的异常分化。有趣的是,在正常细胞的存在下,E6 / E7转导的细胞在2D培养物中增殖更慢,并形成独特的异质上皮结构,在3D培养物中表现出不同程度的扰动,表明共培养正常细胞可能具有抑制作用。本论文开发并提出的系统为研究从扁桃体隐窝纯化的上皮细胞的特定子集及其对E6 / E7感染的反应提供了一种有针对性的方法,为解决许多与扁桃体早期有关的未解决问题奠定了基础肿瘤发生。

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    Kang Sung Yoon Catherine;

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  • 年度 2016
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