Friday, May 9, 2025
5/9/2025
Aging and Rejuvenation of Skin Stem Cells - Project Summary The regenerative capacity of stem cells diminishes as we age. In the case of hair follicle stem cells (HFSCs), this loss manifests as a sustained dormancy phase without regenerating new hair follicles. Although we have gained substantial insight into the molecular differences between young and old stem cells and their niches, a major roadblock in identifying key genes underlying age-related changes in mammals is the lengthy process of generating experimental genetic models (e.g., overexpression or knockout mouse lines) and then aging them—the combination of which delays experiments by years. As such, there is a significant gap in our understanding of the specific genes and pathways that drive age-related changes in HFSCs. Furthermore, although there is evidence suggesting that old stem cells can be rejuvenated, specific genes that can lead to this reversion are unknown. Addressing these knowledge gaps will substantially advance our understanding of stem cell aging and provide a starting point for developing therapies for age-related declines in stem cell functions. This proposal capitalizes on the expertise, tools, and techniques we have established to rapidly test multiple candidates to identify genes that drive or suppress age-related dormancy in HFSCs and delineate the cellular and molecular mechanisms underlying these age-related changes. Findings from us and others show that secreted factors from dermal fibroblasts play a key role in regulating the extended dormancy seen in old HFSCs. We have already nominated one such candidate gene, Gas6, which we have shown can reactivate dormant HFSCs when overexpressed. In Aim 1, we will focus on delineating the cellular and molecular mechanisms by which Gas6 drives HFSCs towards more youthful behavior. In Aim 2, we will aim to identify additional genes that regulate HFSC aging. To enable gene testing in old mice directly and to enhance our throughput, we have established a strategy for rapid, in vivo genetic manipulation directly in old wild-type mice by delivering targeted genetic cargo with adeno-associated viral (AAV) vectors. This strategy provides a practical route to manipulate a relatively large number of genes in vivo, which has previously not been practical in the context of mammalian aging. We will also use SHARE-seq, a powerful method we developed to assess both transcriptome and chromatin changes in the same single cell. We will combine these techniques to gain insight into the cellular and molecular mechanisms by which Gas6 and other genes function to enhance the function of old HFSCs. Collectively, these discoveries will contribute to the basic understanding of stem cell changes that occur with age, provide the research community with much-needed tools to accelerate aging research in vivo, and pinpoint potential genes that can be harnessed to revert or halt age-related defects in HFSCs and beyond.
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