Restoring Melanocyte Stem Cells: A Model of Drug-Mediated Regeneration

项目摘要 增加一个人身体健康的时间，或健康的预期寿命， 通过恢复由于衰老或疾病而丧失或受损的组织功能来实现。开发内源性 干细胞原位修复或替代组织是利用身体先天潜力的理想方法， 复兴前程的与外源性干细胞不同，将内源性干细胞用于再生医学可以减少 需要复杂的，离体细胞重编程和组织工程方案，并消除了 拒绝的风险。然而，在造血系统之外，很少有干细胞功能不全的例子。 在临床中用于治疗目的的原位增强。其中一个原因是，尽管我们知道很多 关于指导生理干细胞功能的调节途径，对最低限度的干细胞功能的了解要少得多。 当干细胞库受损或缺失时，组织再生的细胞和系统需求。在 此外，很少有药理学调节剂被鉴定，使我们能够在原位研究这个问题。 在这里，我们描述了初步的证据表明，我们可以扭转头发变白相关的 使用新药RT 1640的小鼠黑素细胞干细胞损失。头发变白和黑素细胞干细胞是一种 是研究组织再生的理想模型。黑素细胞干细胞存在于毛囊中， 负责再生色素系统和头发生长过程中的毛干色素沉着。由于头发变白 黑素细胞干细胞功能的丧失是可见的和非致命的，黑素细胞干细胞激活可以是 通过简单的拔毛实验诱导，这种干细胞群体对非侵入性的 局部应用于皮肤的治疗剂。利用这一模式，本提案的目标将解决未得到答复的问题， 关于骨诱导原位组织再生的问题。也就是说，我们将确定 体内修复所需的最小生物元素，参与修复的关键细胞类型， 再生反应，以及这种再生药物靶向的关键分子过程。我们将回答 这些问题使用了多种具有已知分子缺陷的毛发变白小鼠模型， 作图和体外组织培养方法。这些研究将提供一个有价值的新例子， 可以通过原位方法实现再生， 逆转人类疾病和衰老影响的机制。

Project Summary Increasing the length of time an individual experiences good health, or a healthy life expectancy, can be achieved by recovering tissue function that is lost or impaired due to aging or disease. Exploiting endogenous stem cells to repair or replace tissues in situ is an ideal approach to harness a body’s innate potential for rejuvenation. Unlike exogenous stem cells, using endogenous stem cells for regenerative medicine reduces the need for complicated, ex vivo cellular reprogramming and tissue engineering protocols, and eliminates the risk of rejection. Outside of the hematopoietic system, however, few examples exist where stem cell function is enhanced in situ for therapeutic purposes within the clinic. One reason for this is that although much is known about regulatory pathways that guide physiological stem cell function, much less is known about the minimum cellular and systemic requirements for tissue rejuvenation when the stem cell pool is damaged or absent. In addition, few pharmacological modulators have been identified to allow us to investigate this question in situ. Here we describe preliminary evidence demonstrating that we can reverse hair graying associated with melanocyte stem cell loss in mice using the novel drug RT1640. Hair graying and melanocyte stem cells are an ideal model for investigating tissue rejuvenation. Melanocyte stem cells reside in the hair follicle and are responsible for regenerating the pigment system and hair shaft pigmentation during hair growth. Gray hair due to loss of melanocyte stem cell function is both visible and non-lethal, melanocyte stem cell activation can be induced experimentally by simply plucking the hair, and this stem cell population is responsive to non-invasive therapeutics applied topically to the skin. Using this model, the aims of this proposal will address unanswered questions regarding pharmacologically induced in-situ tissue rejuvenation. Namely, we will identify the minimum biological elements necessary for in vivo repair, the critical cell types that participate in the regenerative response, and the key molecular processes targeted by this regenerative drug. We will answer these questions using a variety of hair graying mouse models with known molecular defects, in vivo fate mapping, and an in vitro histoculture method. These studies will provide a valuable new example of how tissue rejuvenation can be achieved through an in-situ approach, with significant relevance to understanding mechanisms involved in reversing the effects of disease and aging in humans.