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Specification of Dermal Papilla Cell Fate in the Hair Follicle Stem Cell Niche

毛囊干细胞微环境中真皮乳头细胞命运的规范

基本信息

批准号：
8625707
负责人：
Michael Rendl
金额：
$ 35.59万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8625707
关键词：
Ablation Biological Assay Biological Models Bone Marrow Brain Cells Dermal Development Embryonic Development Epithelial Fibroblasts Future Gene Expression Profiling Gene Targeting Genes Genetic Goals Growth Hair Hair follicle structure Homeostasis Hybrids In Vitro Intestines Invertebrates Knock-out Knowledge Lead Mesenchymal Methods Modeling Molecular Molecular Profiling Morphogenesis Mus Natural regeneration Patients Process Proliferating Regulation Rest Signal Transduction Skin Skin Tissue Specific qualifier value Stem cells Supporting Cell Sweat Glands Testing Therapeutic Uses Tissues Transcriptional Regulation Transplantation Ursidae Family Work burn therapy genome-wide improved in vivo in vivo regeneration knockout gene mouse model novel overexpression programs regenerative regenerative therapy self-renewal skin disorder stem cell fate stem cell niche tongue papilla tool transcription factor

项目摘要

Regulation of stem cell (SC) activation and self-renewal is necessary for successful tissue development and homeostasis. In many tissues this is orchestrated by signals from supporting cells within the microenvironment called the SC niche. A thorough understanding of how mammalian SC niche cells become programmed and function during development to regulate SCs is a crucial requirement for future tissue-specific regenerative therapies. While much knowledge has been gained from studies in invertebrates, a molecular understanding of how niche cells in mammalian SC niches, such as the bone marrow, brain, intestine and hair follicles, acquire their specialized status is unknown due to the complexity of the tissues and the lack of methods to isolate and characterize the cells. We have recently developed novel genetic tools to study dermal papilla (DP) cells in the hair follicle SC niche, which are thought to direct follicular SC fate. We have purified these cells, defined their molecular identity and established assays to study their fate specification. This establishes a much needed mammalian model where formation and function of the SC niche can be studied. Our long- term goal is to understand the molecular mechanisms that govern SC niche fate specification, using hair follicle morphogenesis and regeneration as a model system. Our work has identified the molecular signature of DP cells, including a battery of signaling and transcription factors (TFs). In this proposal, we will test the hypothesis that the DP signature TFs contain the activity necessary and sufficient to regulate the SC activating, hair inducing DP niche fate. We will systematically manipulate signature TF expression in DP cells in vitro and in vivo to define the transcriptional control mechanisms that specify the molecular identity and functional activity of DP niche cells. We will further establish a novel inducible DP-specific in vivo gene targeting mouse model that is currently missing in the field. Finally, we will test with available mice that are targeted for conditional gene ablation, the necessity of candidate DP signature TFs for DP niche fate specification, using this novel in vivo gene ablation model, and in parallel with our established in vitro/in vivo hybrid knockout assay. Our work will identify the core transcriptional regulation of the SC niche fate of hair follicle DP cells. Activating the transcriptional program in isolated DP cells and in regular fibroblasts bears the promise to expand fully functional cells for therapeutic use in skin reconstructive efforts. These findings will have global relevance for other regenerative tissues, where SC niches operate to maintain tissue homeostasis, and potentially will lead to development of 3D-tissue regenerative therapies.

干细胞（SC）活化和自我更新的调节是成功的组织发育和发育所必需的