Resolving the Hierarchy and Regulation of Sebaceous Gland Stem Cells

解决皮脂腺干细胞的层次结构和调控

基本信息

批准号：
10667624
负责人：
Gabriella Rice
金额：
$ 3.53万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667624
关键词：
Ablation Abnormal Keratinocyte Acne Acne Vulgaris Adult Affect Alopecia Atrophic Cell Death Cell Maintenance Cell Proliferation Cell membrane Cells Cessation of life Chronic Cicatrix Color Complex Mixtures Cutaneous Data Disease Environment Functional disorder Genes Genetic Genetic Models Gland Goals Hair Hair Cells Hair Follicle Isthmus Hair follicle structure Histologic Homeostasis Human Image Imaging technology Impairment Individual Knock-out Label Lasers Lead Lesion Lipids Maintenance Mediating Microscopic Molecular Morphogenesis Mus Natural regeneration Organ Pathogenesis Pathology Pathway interactions Patients Persons Physiology Play Population Prevalence Process Production Proliferating Psoriasis Regulation Reporter Research Resolution Role Rupture Sebaceous Glands Sebum Signal Transduction Skin Specific qualifier value Surface Surface Ectoderm System Testing Therapeutic Time Tissues Visualization appendage conditional knockout design experimental study genomic tools imaging approach imaging genetics imaging system in vitro activity in vivo innovation lipid biosynthesis male migration mouse model novel postnatal serial imaging skin disorder stem cell niche stem cell population stem cell self renewal stem cells tool transcription factor two photon microscopy two-photon

项目摘要

PROJECT SUMMARY Sebaceous glands (SGs) are appendages of mammalian skin that produce and secrete a mixture of lipids, known as sebum. Sebum production is crucial for skin maintenance and deviations in normal sebaceous lipid production are implicated in several skin pathologies including acne vulgaris and alopecia. Sebum production is carried out by sebocytes, the constituent cell population of SGs. Sebocytes undergo a unique maturation process which culminates with the rupture of the cell membrane. This process, termed holocrine secretion, facilitates the secretion of sebum from SGs, but consequently results in sebocyte death. As lipid turnover is a function of sebocyte turnover, sebocyte replenishment is critical to the functional maintenance of SGs. The lifelong turnover of sebocytes requires a continuous supply of cells to replenish and maintain the gland, which suggests the involvement of stem cells in the maintenance of SG tissues. However, the intrinsic and extrinsic mechanisms that regulate activity of the presumptive SG stem cells are not well defined. This is in part due to the limitations of static histological analyses. Such experimental approaches can only capture single snapshots in time, which are insufficient for delineating a hierarchical organization in a tissue with a rapid turnover rate. Furthermore, the overlapping expression of stem cell-associated genes, like Sox9, between the hair follicle and SGs has limited our ability to interpret the functional role of these markers in SG physiology uncoupled from the hair. To overcome these limitations, I have combined genetic lineage-tracing tools with live imaging approaches based on two- photon microscopy. The overall goal of this study is to implement an integrative approach by combining a live imaging system with state-of-the-art genomics tools to 1) characterize stem cell dynamics in SG homeostasis and regeneration by live imaging, and 2) analyze how sebocyte fate is influenced by the key molecular signal, Sox9. In my preliminary experiments, I found that cells from the hair follicle isthmus, an adjacent compartment, made cell contributions to SGs, and that skin-specific knockouts of Sox9 resulted in SG atrophy. I hypothesize that sebocytes are replenished by a heterogeneous stem cell population from the isthmus and that SOX9 is required for their regulation and SG physiology. Aim 1 of this proposal is designed to resolve the sebocyte lineage hierarchy and test the necessity of the isthmus in SG regeneration. Aim 2 of this proposal will address the functional role of SOX9 in regulating sebocyte fate. This research offers an innovative approach to study SG stem cells within the natural tissue environment by combining cutting-edge imaging technologies and genetic tools. The goal of this proposal is to uncover the fundamental mechanisms of SG maintenance by resolving the sebocyte lineage and molecular pathways that regulate SG stem cell activity in the skin.

项目概要皮脂腺 (SG) 是哺乳动物皮肤的附属物，可产生和分泌脂质混合物，已知作为皮脂。皮脂生成对于皮肤保养和正常皮脂脂质生成的偏差至关重要与多种皮肤病有关，包括寻常痤疮和脱发。皮脂产生进行皮脂腺细胞（SG 的组成细胞群）。皮脂细胞经历独特的成熟过程随着细胞膜的破裂而达到顶峰。这个过程被称为全分泌，促进 SG 分泌皮脂，但最终导致皮脂细胞死亡。由于脂质周转率是皮脂细胞更新、皮脂细胞补充对于 SG 的功能维持至关重要。终生营业额皮脂腺细胞需要持续供应细胞来补充和维持腺体，这表明干细胞参与 SG 组织的维护。然而，内在机制和外在机制调节假定的 SG 干细胞活性的机制尚不明确。这部分是由于限制静态组织学分析。这种实验方法只能及时捕获单个快照，这不足以在快速更替率的组织中描绘等级组织。此外，毛囊和 SG 之间干细胞相关基因（如 Sox9）的重叠表达受到限制我们有能力解释这些标记在与头发无关的 SG 生理学中的功能作用。克服这些限制，我将遗传谱系追踪工具与基于两种的实时成像方法结合起来：光子显微镜。本研究的总体目标是通过结合现场实践来实施综合方法具有最先进基因组学工具的成像系统，1) 表征 SG 稳态中的干细胞动力学和通过实时成像再生，2) 分析关键分子信号如何影响皮脂细胞的命运，红袜9.在我的初步实验中，我发现来自毛囊峡部（相邻的隔室）的细胞，细胞对 SG 做出了贡献，并且皮肤特异性敲除 Sox9 导致 SG 萎缩。我假设皮脂腺细胞由来自峡部的异质干细胞群补充，SOX9 是它们的调节和 SG 生理学所需。该提案的目标 1 旨在解决皮脂细胞问题谱系层次并测试峡部在 SG 再生中的必要性。该提案的目标 2 将解决 SOX9 在调节皮脂细胞命运中的功能作用。这项研究提供了一种研究 SG 的创新方法通过结合尖端成像技术和遗传技术，在自然组织环境中产生干细胞工具。该提案的目标是通过解决以下问题来揭示 SG 维护的基本机制：皮脂细胞谱系和调节皮肤 SG 干细胞活性的分子途径。