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

• 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
• 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

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.

摘要 成人皮肤毛囊间表皮（IFE）更新目前是由简单的模型， 相对同质的基底干/祖细胞。然而，综合实地演练可能会长期延续， 由复杂组织结构的生理需求协调，所述复杂组织结构包括多个 异质性水平。我们开始阐明两种细胞的细胞和分子组织， 空间上不同的IFE结构域，它们的生理相关性，以及小鼠之间的关系 人的皮肤。我们证明了小鼠尾基底膜的分子和细胞状态 微域（尺度和尺度间）概括了人类皮肤IFE在网中的空间组织， 脊和脊间。我们开始发现皮肤空间的生理相关性 领域：适应不同的紫外线照射。我们发现多个IFE人群具有不同的 克隆分析中的行为，并描述了第一个在体内表皮传递放大（TA）细胞。的 后来唯一地显示了一个成熟依赖的行为，从一个 放大阶段到消光阶段。这为分子生物学的研究开辟了一条新的途径 从“年轻”到“成熟”细胞状态的定时转换机制。利用老鼠遗传学，我们 开发新的工具来标记和表征最受紫外线照射的IFE域，并检查 深入研究：（1）IFE在皮肤及其生理组织中的空间异质性和域组织 显著性;和（2）皮肤中IFE干/TA群体行为的异质性， 与空间域的再生能力有关，细胞命运的机制是什么？ 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。我们建议 基底细胞状态、多个干细胞/TA细胞群体和空间分布的异常IFE复杂性， 组织可以解释皮肤稳态的异常鲁棒性， 不断的环境挑战。