Defining the heterogeneity of cell lineages in the inter-follicular epidermis

定义毛囊间表皮细胞谱系的异质性

基本信息

批准号：
10596423
负责人：
Tudorita Tumbar
金额：
$ 55.98万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-12 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596423
关键词：
3-Dimensional Acute Adult Architecture Area Basal Cell Behavior Biological Cell Lineage Cell Proliferation Cell Survival Cell model Cells Complex Data Development Epidermal Ridges Epidermis Extinction Genetic Growth Heterogeneity Homeostasis Human Injury Label Laboratories Light Link Lymphatic Modeling Molecular Mus Natural regeneration Pattern Phase Physiological Population Proliferating Regenerative capacity Research SOX6 gene Science Shapes Signal Transduction Skin Skin wound healing Spatial Distribution Stratum Basale Structure Study models Tail Time Tissues UV Radiation Exposure UV induced UV response Work behavior change cell type epidermal stem cell in vivo injury and repair molecular domain mouse genetics novel progenitor regeneration potential regenerative regenerative cell response skin organogenesis skin regeneration stem stem cell population stem cells tool transcription factor transcriptomics

项目摘要

Abstract Adult skin interfollicular epidermis (IFE) renewal is currently described by simple models of relatively homogenous basal stem/progenitor cells. However, long-term IFE renewal is likely orchestrated by the physiological demands of a complex tissue architecture comprising multiple levels of heterogeneity. We began to elucidate the cellular and molecular organization of two spatially distinct IFE domains, their physiological relevance, and the relationship between mouse and human skin. We demonstrate that molecular and cellular states of mouse tail basal microdomains (scales and inter-scales) recapitulate human skin IFE spatial organization in rete ridges and inter-ridges. We begin to uncover a physiological relevance for the skin spatial domains: adaptation to differential UV exposure. We identify multiple IFE populations with distinct behavior in clonal analysis and describe the first in vivo epidermal transit-amplifying (TA) cell. The later uniquely displays a maturation-dependent behavior with a timed-transition from an amplification phase to an extinction phase. This opens-up a new road for investigating molecular mechanisms of timed transitions from a ‘young’ to a ‘mature’ cell state. Using mouse genetics, we develop new tools to label and characterize IFE domains that are most UV exposed and examine in depth: (1) IFE spatial heterogeneity and domain organization in skin and its physiological significance; and (2) the heterogeneity of IFE stem/TA population behavior in skin, how this relates to regeneration capacity of spatial domains, and what are the mechanisms of cell fate transition from a young to a mature TA cell state, and from a stem to a TA cell. We propose that the extraordinary IFE complexity of basal cell states, multiple stem/TA cell populations, and spatial organization may explain the unusual robustness of skin homeostasis in response to constant environmental challenges.

抽象的成人皮肤滤泡间表皮（IFE）更新目前通过简单的模型来描述相对同质的基底干/祖细胞然而，长期的 IFE 更新是可能的。由复杂组织结构的生理需求精心策划，该组织结构包括多个我们开始阐明两者的细胞和分子组织。空间上不同的 IFE 域、它们的生理相关性以及小鼠之间的关系我们证明了小鼠尾部基底的分子和细胞状态。微域（尺度和尺度间）在 rete 中概括了人类皮肤 IFE 空间组织我们开始揭示皮肤空间的生理相关性。领域：对不同紫外线暴露的适应我们确定了具有不同特征的多个 IFE 群体。克隆分析中的行为并描述了第一个体内表皮转运放大（TA）细胞。后来独特地表现出一种成熟依赖的行为，具有从这为研究分子开辟了一条新的道路。我们利用小鼠遗传学，研究了从“年轻”细胞状态到“成熟”细胞状态的定时转变机制。开发新工具来标记和表征最受紫外线照射的 IFE 域并进行检查深入：（1）皮肤及其生理学中的IFE空间异质性和域组织 (2) 皮肤中 IFE 干/TA 群体行为的异质性，这是如何实现的？与空间域的再生能力有关，细胞命运的机制是什么我们提出从年轻到成熟 TA 细胞状态的转变，以及从干细胞到 TA 细胞的转变。基底细胞状态、多个干/TA 细胞群和空间的非凡 IFE 复杂性组织可以解释皮肤稳态响应的异常稳健性持续的环境挑战。