Live Imaging of Skin Regeneration

描述（由申请人提供）：组织稳态和再生是由干细胞维持的，干细胞既可以补充自己的祖细胞库，也可以在组织的整个生命周期中产生分化细胞。干细胞所处的环境，即所谓的生态位，调节着它们的特殊能力。干细胞调控是组织功能的关键。不能正确激活干细胞会阻碍组织修复，导致器官衰竭，而干细胞激活不当会导致过度生长和癌症。因此，研究干细胞及其壁龛的基本阐明可能对一系列疾病的治疗具有无价之宝。我们仍然缺乏干细胞调控的动态机制的关键知识。获得这些知识的主要障碍之一是缺乏一个明确定义的生态位，在这个生态位中，可以观察和操纵再生的离散步骤。我实验室研究的目标是了解控制干细胞的细胞和信号机制，以及在疾病状态下出现的问题。为了理解干细胞生物学的这些基本原理，我们利用了皮肤毛囊内独特的哺乳动物干细胞生态位，因为它具有特殊的可及性和明确的结构。我的实验室已经建立了一种体内策略来可视化毛囊干细胞生态位的组成部分，以便操纵它们并明确地询问哪些信号，当被破坏时，会引起疾病。使用一种新颖的，非侵入性的，双光子成像方法，我们实时跟踪活小鼠毛囊的干细胞生态位。通过这些方法，我们研究了上皮干细胞及其后代在生理性毛发再生过程中的行为以及间充质生态位如何影响它们的行为。本提案的目标是使用尖端成像技术，遗传操作和细胞生物学的综合方法来推进我们对激活干细胞和维持组织再生机制的理解。这些实验将是揭示干细胞生态位成分在体内实时动态的关键。鉴于小生境成分和信号传导已被证明在其他器官中是保守的，我们关于控制干细胞的基本原理的发现可能与其他组织相关，并将推进疾病治疗的治疗策略。

DESCRIPTION (provided by applicant): Tissue homeostasis and regeneration are sustained by stem cells, which are cells able to both replenish their own progenitor cell pool as well as give rise to differentiated cells throughout the life of a tissue. The environment in which stem cells reside, the so-called niche, regulate their special abilities. Stem cell regulation is key fo tissue function. Failure to properly activate stem cells will hinder tissue repair and lead to orga failure, while improper stem cell activation will lead to overgrowth and cancer. Therefore, the basic elucidated in researching stem cells and their niches may be invaluable in moving towards cures for a range of diseases. We still lack critical knowledge of the dynamic mechanisms of stem cell regulation. One of the major obstacles to gaining that knowledge is lack of access to a well-defined niche in which the discrete steps of regeneration can be observed and manipulated. The goal of my laboratory research is to understand the cellular and signaling mechanisms that govern stem cells and what goes awry in a disease state. To understand these fundamental principles of stem cell biology, we make use of the unique mammalian stem cell niche within the skin hair follicle because of its exceptional accessibility and well-defined structure. My laboratory has established an in vivo strategy to visualize the components of the hair follicle stem cell niche, in order to manipulate them and to ask specifically which signals, when disrupted, give rise to disease. Using a novel, non-invasive, two-photon imaging approach we follow the stem cell niche of the hair follicle in real-time in live mice. By these means, we have studied the behavior of the epithelial stem cells and their progeny during physiological hair regeneration and how the mesenchymal niche influences their behavior. The goal of this proposal is to use an integrated approach of cutting edge imaging technology, genetic manipulation and cell biology to advance our understanding of the mechanisms that activate stem cells and sustain tissue regeneration. These experiments will be key to reveal the dynamics of stem cell niche components in vivo in real time. Given that niche components and signaling have been shown to be conserved in other organs, our findings about the fundamental principles that govern stem cells will likely be relevant to other tissues, and will advance therapeutic strategies for the cure of diseases.