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

摘要 成人皮肤毛囊间表皮(IFE)的更新目前由简单的模型描述 相对同质的基本干/祖细胞。然而，长期的IFE续签是可能的 由复杂的组织体系结构的生理需求编排，包括 异质性水平。我们开始阐明两种病毒的细胞和分子结构 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 和人类的皮肤。我们证明了小鼠尾巴的分子和细胞状态 微域(尺度和尺度间)概括了人类皮肤在网格中空间组织 山脊和山脊间。我们开始揭示皮肤空间的生理关联 领域：适应不同的紫外线照射。我们确定了多个具有不同特征的IFE群体 在克隆分析中的行为，并描述了体内第一个表皮传递放大(TA)细胞。这个 LATH唯一地显示依赖于成熟的行为，并从 从放大阶段到消光阶段。这开辟了一条研究分子的新道路 从“年轻”到“成熟”细胞状态的定时转换机制。利用老鼠的遗传学，我们 开发新工具来标记和表征紫外线暴露最多的IFE区域并进行检查 深入研究：(1)皮肤中IFE的空间异质性和区域组织及其生理意义 意义；以及(2)IFE干细胞/TA群体行为在皮肤中的异质性，这是如何 与空间域的再生能力有关，以及细胞命运的机制是什么 从年轻的TA细胞状态过渡到成熟的TA细胞状态，从干细胞过渡到TA细胞。我们建议 基本细胞状态、多个干细胞/TA细胞群体和空间的非凡生命复杂性 组织可能会解释皮肤动态平衡对 持续不断的环境挑战。

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.