Hair follicle bulge cells in tumorigenesis and alopecia

肿瘤发生和脱发中的毛囊凸出细胞

• 批准号: 7929359
• 负责人: GEORGE COTSARELIS
• 金额: $ 25.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2011-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929359
• 关键词: Alopecia; Applications Grants; Basal cell carcinoma; Biological Assay; Candidate Disease Gene; Cell Count; Cell Cycle; Cell Separation; Cell Surface Proteins; Cells; Characteristics; Chronic; Cornea; Cutaneous; Disease; Dominant-Negative Mutation; Epidermis; Epithelial; Epithelium; Funding; Future; Gene Expression; Generations; Genes; Germ; Goals; Hair; Hair Follicle Neoplasm; Hair follicle structure; Hair shaft structure; Human; Keratin; Molecular; Molecular Analysis; Mus; Natural regeneration; Nature; Pathway interactions; Patients; Pattern; Phenotype; Plant Roots; Play; Positioning Attribute; Property; RU-486; Research; Role; Sebaceous Glands; Skin; Skin Physiology; Specificity; Stem cells; System; Testing; Tissues; Transgenic Mice; Wound Healing; base; cDNA Arrays; carcinogenesis; gene discovery; gene function; insight; overexpression; progenitor; promoter; protein expression; reconstitution; self-renewal; skin disorder; stem; stem cell biology; tumorigenesis

DESCRIPTION (provided by applicant): The long term goal of this project is to better understand epithelial stem cell biology. Epithelial stem cells are responsible for the regeneration of self-renewing tissues such as epidermis, hair follicle, and cornea. We originally identified putative epithelial stem cells in the bulge of the hair follicle. We then isolated a keratin 15 promoter that targets bulge cells in transgenic mice. The K15 promoter allowed for the isolation, lineage analysis and molecular characterization of hair follicle stem cells. We showed, that bulge cells have properties of stem cells, and isolated bulge cells can reconstitute hair follicles, epidermis and sebaceous glands. We have now identified a number of genes which we hypothesize maintain the stem cell phenotype. In this grant application we will: 1. evaluate whether genes upregulated in the bulge cells are important for maintaining the hair follicle stem cell phenotype by: a. overexpressing candidate genes in non-hair follicle stem cells of transgenic mice, and then testing whether these cells behave as hair follicle stem cells. b. blocking candidate gene pathways specifically in the bulge cells using our Kl5CrePrl mice to delete or overexpress genes specifically in the bulge cells. 2. determine if genes downregulated in telogen bulge cells are involved in stem cell activation and/or lineage determination by: a. generating inducible transgenic mice in which candidate genes are over-expressed in bulgecells using an RU486 inducible system, and b. deleting candidate "bulge activation" or lineage determining genes specifically in bulge cells and their progeny using theKlSCrePR l mice. 3. develop means for isolating and characterizing human hair follicle stem cells. a. We will establish whether genes identified in mouse bulge are also expressed in human bulges. b. We will delineate hair follicle stem and progenitor cells within both the mouse and human hair follicle based on cell surface protein expression patterns. These distinct subpopulations of cells within the hair follicle will be isolated by fluorescent activated cell sorting, and their stem cell nature, gene expression patterns and functional characteristics will be discerned. Patients with alopecia, hair shaft disorders, basal cell carcinoma, hair follicle tumors, or chronic wounds could potentially benefit from this research.

描述（由申请人提供）：该项目的长期目标是更好地了解上皮干细胞生物学。上皮干细胞负责表皮、毛囊和角膜等自我更新组织的再生。我们最初在毛囊的隆起处发现了假定的上皮干细胞。然后我们分离出一个角蛋白 15 启动子，该启动子针对转基因小鼠的凸出细胞。 K15 启动子可用于毛囊干细胞的分离、谱系分析和分子表征。我们发现，凸出细胞具有干细胞的特性，分离的凸出细胞可以重建毛囊、表皮和皮脂腺。我们现在已经鉴定了许多我们假设维持干细胞表型的基因。在此拨款申请中，我们将： 1. 通过以下方式评估凸起细胞中上调的基因对于维持毛囊干细胞表型是否重要： 一个。 在转基因小鼠的非毛囊干细胞中过度表达候选基因，然后测试这些细胞是否具有毛囊干细胞的行为。 b. 使用我们的 Kl5CrePrl 小鼠，特别是在凸出细胞中阻断候选基因途径，以删除或过度表达特定在凸出细胞中的基因。 2. 通过以下方式确定休止期凸出细胞中下调的基因是否参与干细胞激活和/或谱系决定： 一个。使用RU486诱导系统产生可诱导的转基因小鼠，其中候选基因在凸出细胞中过度表达，并且 b.使用KlSCrePR1小鼠特异地删除凸出细胞及其子代中的候选“凸出激活”或谱系决定基因。 3.开发分离和表征人类毛囊干细胞的方法。 一个。我们将确定在小鼠凸起中发现的基因是否也在人类凸起中表达。 b.我们将根据细胞表面蛋白表达模式描绘小鼠和人类毛囊内的毛囊干细胞和祖细胞。毛囊内这些不同的细胞亚群将通过荧光激活细胞分选来分离，并且将辨别它们的干细胞性质、基因表达模式和功能特征。 患有脱发、毛干疾病、基底细胞癌、毛囊肿瘤或慢性伤口的患者可能会从这项研究中受益。

项目成果

Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding.

来自真皮 γδ T 细胞的 Fgf9 在受伤后诱导毛囊新生。

• 发表时间: 2013-07
• 影响因子: 82.9
• 作者: Gay, Denise;Kwon, Ohsang;Zhang, Zhikun;Spata, Michelle;Plikus, Maksim V;Holler, Phillip D;Ito, Mayumi;Yang, Zaixin;Treffeisen, Elsa;Kim, Chang D;Nace, Arben;Zhang, Xiaohong;Baratono, Sheena;Wang, Fen;Ornitz, David M;Millar, Sarah E;Cotsare
• 通讯作者: Cotsare

Epidermal cells rev up reprogramming.

表皮细胞加速重新编程。

• 发表时间: 2008-11
• 影响因子: 46.9
• 作者: Gadue, Paul;Cotsarelis, George
• 通讯作者: Cotsarelis, George

Is the hair follicle necessary for normal wound healing?

毛囊是正常伤口愈合所必需的吗？

• DOI: 10.1038/jid.2008.86
• 发表时间: 2008-05-01
• 期刊: The Journal of investigative dermatology
• 作者: Mayumi Ito;G. Cotsarelis
• 通讯作者: G. Cotsarelis

Erratum: Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis (Nature Medicine (2005) 11 (1351-1354))

勘误表：毛囊凸起中的干细胞有助于伤口修复，但无助于表皮的稳态（Nature Medicine (2005) 11 (1351-1354)）

• DOI: 10.2514/3.10183
• 发表时间: 2024-09-13
• 期刊: Nature Medicine
• 影响因子: 82.9
• 作者: Mayumi Ito;Yaping Liu;Zaixin Yang;Jane Q. Nguyen;Fan Liang;R. Morris;G. Cotsarelis
• 通讯作者: G. Cotsarelis

Review of hair follicle dermal cells.

毛囊真皮细胞的回顾。

• DOI: 10.1016/j.jdermsci.2009.11.005
• 发表时间: 2010-01
• 期刊: Journal of dermatological science
• 影响因子: 4.6
• 作者: Yang CC;Cotsarelis G
• 通讯作者: Cotsarelis G