Investigating the mechanisms of hair progenitor cell activation and aging resistance through SOX5

The National Institute on Aging awarded the University of Pennsylvania $164,190 under the Aging Research program (CFDA 93.866) on August 6, 2026, to investigate the mechanisms of hair progenitor cell activation and aging resistance through the transcription factor SOX5.

The recipient will conduct molecular and cellular research to determine whether SOX5 is required for hair follicle stem and progenitor cell activation during the anagen (growth) phase and whether it protects against age-related hair loss. Prior work identified SOX5 as specifically expressed in activated progenitor cells at anagen onset within the secondary hair germ and throughout the proliferative lower matrix during the growth phase. In vitro overexpression of SOX5 in primary human keratinocytes significantly enhanced proliferation. The funded research will test the hypothesis that SOX5 induces anagen entry and confers aging resistance by regulating hair matrix cell proliferation and directing secondary hair germ cells toward follicular lineage commitment.

Place of performance is Philadelphia, Pennsylvania. The period of performance runs through February 28, 2029. The Aging Research program supports biomedical, social, and behavioral research directed toward understanding the aging process and diseases and special problems of older adults, with particular emphasis on Alzheimer's disease and related dementias.

Abstract

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.