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

项目总结

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.