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.

抽象的 成人皮肤互口间表皮（IFE）更新目前是通过简单模型来描述的 相对同质的碱性干/祖细胞。但是，长期更新可能是 由复杂的组织建筑的物理需求精心策划的多个 异质性水平。我们开始阐明两个的细胞和分子组织 在空间上不同的IFE域，它们的身体相关性以及鼠标之间的关系 和人类皮肤。我们证明了小鼠尾巴的分子和细胞态碱性 微区（量表和尺度）在rete中概括了人体皮肤 山脊和河间。我们开始发现皮肤空间的物理相关性 域：适应不同的紫外线暴露。我们确定多个IFE人群 克隆分析中的行为，并描述第一个体内表皮转运式扩增（TA）细胞。这 后来独特地显示出与成熟的行为，并从 扩增阶段至扩展阶段。这为研究分子开辟了一条新的道路 从“年轻”到“成熟”细胞状态的定时过渡的机制。使用鼠标，我们 开发新工具来标记和表征最紫外线的IFE域并检查 深度：（1）皮肤中的空间异质性和领域组织及其生理 意义; （2）皮肤中IFE茎/TA种群行为的异质性，这是如何 与空间结构域的再生能力有关，细胞脂肪的机制是什么 从年轻的TA细胞状态，从茎到TA细胞的过渡。我们提出了这一点 基本细胞状态，多个茎/TA细胞群和空间的非凡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。