Decipher the immunemodulatory functions of epithelial stem cells during wound repair

About This Grant

PROJECT SUMMARY Wound healing is a critical physiological process essential for restoring tissue homeostasis from damage and infections. However, many aged people or individuals with chronic conditions often experience delayed or defective wound repair. In the United States alone, these nonhealing wounds cause significant economic burdens, incurring more than $25 billion annually in healthcare costs. A major gap contributing to this issue is the incomplete understanding of complex cellular interactions during wound healing. Cutaneous wound repair is primarily mediated by the epithelial stem cells within the epidermis and hair follicles, whose regeneration and differentiation capacity are supported by diverse cell types forming their niche. While immune cells play pivotal roles in infection control and debris removal, the inflammatory conditions can impair stem cell function. Thus, how epithelial stem cells achieve self-renewal and differentiation within a highly inflammatory environment in injured tissues remains unclear. Addressing this gap is pivotal for advancing our knowledge of immune tolerance, barrier integrity, and wound repair biology. This proposal aims to elucidate how epithelial stem cells modulate their immunological niche to adapt to inflammatory environments and drive wound repair. Our preliminary data indicate that upon injury, the epithelial stem cells residing in the hair follicles activate robust immune-modulatory capabilities, such as upregulating CD80 expression. Importantly, these cells employ this capacity to establish close interactions with regulatory T (Treg) cells, forming a protective niche in the wound site that shields hair follicle stem cells from inflammatory damage. Moreover, we discovered an unconventional mechanism that can directly induce and maintain Foxp3 expression in wound-infiltrating effector T cells. Based on these preliminary findings, we hypothesize that: hair follicle stem cells induce effector T cells within wounds to directly differentiate into Treg cells, which build a protective niche and regulate inflammatory responses crucial for epithelial stem cell function during wound repair. Built on this hypothesis, our first objective is to identify the precursors of Treg cells induced during wound healing. Next, we will delineate the receptors on T cells that respond to CD80 signals from epithelial stem cells to drive Treg induction. Last, we will elucidate the molecular mechanisms by which CD80 stabilizes Foxp3 expression in effector T cells. Together, these studies will unveil a non-canonical mechanism of Treg induction and shed light on the remarkable immune modulatory activity of epithelial stem cells during wound repair. Ultimately, this work may uncover new strategies for improving non-healing wounds.