Investigating the Mechanisms of Hair Progenitor Cell Activation and Aging Resistance Through SOX5

Adult tissue homeostasis depends on the tightly regulated activity of tissue-resident stem and progenitor cells. With age, this regenerative capacity declines due to impaired progenitor function, contributing to tissue dysfunction and degeneration. One of the most striking examples of this occurs in the hair follicle, a highly regenerative mini-organ that undergoes cyclical phases of growth (anagen) and rest (telogen). Aging disrupts the cycle by prolonging telogen and diminishing the proliferative output of progenitor cells, ultimately leading to follicle miniaturization and hair loss. Despite its clinical relevance, the molecular mechanisms governing progenitor cell activation and maintenance in the hair follicle remain incompletely understood. To address this gap, I performed single-cell RNA sequencing analysis, RNA velocity analysis, and immunofluorescence staining of cycling postnatal mouse skin, identifying SOX5 as a transcription factor specifically expressed in the earliest subset of activated progenitor cells at anagen onset, localized to a key structure known as the secondary hair germ (SHG). Expression then persists throughout the anagen phase within the proliferative lower matrix before becoming undetectable until the next cycle, suggesting a temporally restricted role in activating progenitor cells and guiding their commitment to a follicular lineage. Supporting this, in vitro overexpression of SOX5 in primary human keratinocytes significantly enhances proliferation, pointing to SOX5 as a central regulator of proliferative dynamics during follicular regeneration. Based on these findings, I hypothesize that SOX5 induces anagen and protects the hair follicle against aging by regulating proliferation of the hair matrix cells and directing SHG cells towards a hair follicle lineage fate. In Aim 1, I will determine whether SOX5 is required for SHG activation and sufficient to initiate early lineage specification. I will also evaluate whether SOX5 overexpression reprograms human keratinocytes toward a follicular identity. In Aim 2, I will assess the role of SOX5 in maintaining matrix proliferation and hair follicle structure during aging using a combination of ex vivo human hair follicle organ culture and a transgenic Sox5 overexpression mouse model. By elucidating how SOX5 governs progenitor cell activation and maintenance, this work may uncover therapeutic strategies to restore hair progenitor cell function in aging and hair loss disorders. More broadly, it will contribute to our understanding of how tissue-specific progenitor programs can be leveraged to counteract age-related regenerative decline. Project Number: 1F30AG099347-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Jack You | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $55,114 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F10B-Q (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11313932