Control of epithelial plasticity and differentiation in hair follicle stem/progenitor cells

毛囊干/祖细胞上皮可塑性和分化的控制

• 批准号: 9293894
• 负责人: Xing Dai
• 金额: $ 33.99万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-22 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293894
• 关键词: Acute; Adult; Anatomy; Atopic Dermatitis; Attention; Beds; Behavior; Biology; Cancer Biology; Cancer Etiology; Cancerous; Cell Culture Techniques; Cell Cycle; Cell Separation; Cells; Chronic; Clinical; Data; Dermal; Development; Disease; Electron Microscopy; Embryo; Ensure; Epidermis; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Event; Experimental Models; Failure; Foundations; Funding; Gene Expression; Genetic; Genetic Transcription; Hair; Hair follicle structure; Homeostasis; In Vitro; Injury; Knock-out; Knowledge; Laboratories; Lead; Life; Light; Location; Maintenance; Malignant Neoplasms; Mammary gland; Mediating; Mesenchymal; Mesoderm; Methodology; Modeling; Modernization; Molecular; Molecular Target; Morphogenesis; Morphology; Mus; Natural regeneration; Neoplasm Metastasis; Neural Crest; Pathologic; Phase; Phenotype; Physiological; Play; Process; Property; Proteins; Regulation; Repression; Research; Rest; Role; Self-control as a personality trait; Signal Transduction; Skin; Skin Cancer; Skin wound; Specific qualifier value; Stem cells; System; Techniques; Testing; Tissues; Transplantation; Work; Wound Healing; adult stem cell; cell behavior; cell type; design; epithelial to mesenchymal transition; in vivo; injury and repair; insight; loss of function; mouse model; mutant; novel; overexpression; permissiveness; preference; premature; programs; public health relevance; regenerative; repaired; self-renewal; skin disorder; skin organogenesis; stem; stem cell biology; stem cell fate; stem cell therapy; tongue papilla; tool; trait; transcription factor; wound

 DESCRIPTION (provided by applicant): Fueled by stem cells, skin epithelia self-renew throughout adult life. The long-term objectives of this research are to elucidate the genetic and molecular mechanisms that regulate skin development, homeostasis and regeneration, and to gain insights into how such control mechanisms go awry in skin diseases such as atopic dermatitis and cancer. Proper stem cell behaviors are key to the execution of normal regenerative programs and their misregulation underlies diseased conditions. Intricate control of gene expression sits at the very center of stem cell regulation, and for this reason we have focused our attention on transcriptional regulators. Past research in the laboratory supported by R01 AR047320 had presented Ovol transcription factors as excellent candidates for controlling the fate of skin epithelial stem and progenitor cells. Funding was discontinued at the last renewal, but exciting new data now poise us to probe into a previously under- appreciated territory of skin stem cell control. Surprisingly, both hair follicle and interfollicular epidermal stem/progenitor cells use Ovol factors to suppress their intrinsic tendency to undergo molecular and/or morphological changes that can ultimately lead to conversion into mesenchymal cell types (epithelial-to- mesenchymal transition or EMT) under permissive conditions. The tools and findings that we generated have laid a strong foundation for us to next ask how developmental progenitor cells and adult stem cells in the hair follicles balance their lineage plasticity with epithelial terminal differentiation to achieve normal morphogenesis and regeneration. Specifically, we ask the following questions in this application: 1) Is active suppression of EMT-like events essential for the morphogenesis and differentiation of embryonic hair follicle progenitor cells? 2) Do similar control mechanisms also operate in adult hair follicle stem cells during physiological hair regeneration? 3) Is the intrinsic EMT tendency of skin epithelial cells important for them to acquire expanded lineage potential during injury repair and how is this tendency kept in check to maintain epithelial differentiation? We will combine classical mouse genetics (conditional knockout and inducible overexpression) with modern techniques such as cell sorting, transcriptional profiling, lineage tracing, and ex vivo stem cell cultures to investiate the plasticity and differentiation of hair follicle stem/progenitor cells during morphogenesis and regeneration, under wild-type and mutant conditions.

 描述(申请人提供)：在干细胞的推动下，皮肤上皮细胞在整个成年生活中自我更新。这项研究的长期目标是阐明调节皮肤发育、体内平衡和再生的遗传和分子机制，并深入了解这些控制机制在特应性皮炎和癌症等皮肤病中是如何出错的。正确的干细胞行为是执行正常再生程序的关键，而它们的错误调控是疾病条件的基础。错综复杂的基因表达控制是干细胞调控的核心，为此，我们将注意力集中在转录调控上。过去由R01 AR047320支持的实验室研究表明，OVOL转录因子是控制皮肤上皮干细胞和祖细胞命运的极佳候选者。上一次更新时停止了资助，但令人兴奋的新数据现在让我们准备好探索之前被低估的皮肤干细胞控制领域。令人惊讶的是，毛囊和毛囊间表皮 干细胞/祖细胞使用OVOL因子抑制其固有的发生分子和/或形态变化的倾向，这些变化最终可能导致在允许的条件下转化为间充质细胞类型(上皮向间充质转化或EMT)。我们生成的工具和发现为我们下一步研究毛囊中的发育前体细胞和成体干细胞如何平衡其谱系可塑性和上皮末端分化以实现正常的形态发生和再生奠定了坚实的基础。在这一应用中，我们特别提出以下问题：1)主动抑制EMT样事件对于胚胎毛囊前体细胞的形态形成和分化是必不可少的吗？2)在生理性毛发再生过程中，类似的控制机制是否也在成年毛囊干细胞中起作用？3)皮肤上皮细胞固有的EMT倾向对它们在损伤修复过程中获得扩展的谱系潜力是否重要，以及如何控制这种趋势以维持上皮分化？我们将结合经典的小鼠遗传学(条件基因敲除和诱导过表达)与现代技术，如细胞分选、转录图谱、谱系追踪和体外干细胞培养，来研究毛囊干/祖细胞在野生型和突变型条件下形态发生和再生过程中的可塑性和分化。