The long-term goal of this project is to develop better treatments for wounds, alopecias and other degenerative skin disorders by elucidating the cellular and molecular mechanisms of skin regeneration following wounding. We demonstrated that adult mice have the capacity to regenerate hair follicles, sebaceous glands and fat following a full thickness wound. We have evidence that Wnt, Fgf, Hh pathways and gamma/delta T cells are vital players controlling this wound induced hair follicle neogenesis (WIHN). We hypothesize that manipulation of these molecular pathways at the right time and place will convert non-regenerative tissue into regenerative tissue with the ability to form hair follicles, sebaceous glands and fat in response to wounding. To test this hypothesis, we will determine: 1. The role of dermal Wnt/ss-catenin signaling in hair follicle neogenesis using transgenic and conditional knockout mice, 2. The cellular origin of nascent hair follicles in the wound using promoters targeting fibroblasts, myofibroblasts, hair follicle dermal papilla and other dermal subpopulations for lineage analysis, 3. The role of sonic hedgehog signaling in the ability to coax healing wounds to regenerate rather than scar. Human skin xenografted to immunodeficient mice will be studied for its ability to respond with follicular neogenesis to Wnt and/or Shh activation. Ultimately, our findings will yield insights into scarless wound healing tht have implications for understanding skin biology and developing future treatments for wounds, alopecia and other degenerative skin disorders.
Scars typically lack hair follicles. We are developing ways to regenerate hair follicles after wounding by taking advantage of genetically manipulated mice that heal with little scarring. These studies will ultimately benefit people with wounds, scars, alopecias and other degenerative skin disorders.
|Lim, Chae Ho; Sun, Qi; Ratti, Karan et al. (2018) Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing. Nat Commun 9:4903|
|Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752|
|Ali, Niwa; Zirak, Bahar; Rodriguez, Robert Sanchez et al. (2017) Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation. Cell 169:1119-1129.e11|
|Ellebrecht, Christoph T; Bhoj, Vijay G; Nace, Arben et al. (2016) Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353:179-84|
|Xie, Lin; Yang, Ruifeng; Liu, Shujing et al. (2016) TR3 is preferentially expressed by bulge epithelial stem cells in human hair follicles. Lab Invest 96:81-8|
|Yang, Guangrui; Chen, Lihong; Grant, Gregory R et al. (2016) Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival. Sci Transl Med 8:324ra16|
|Gay, Denise L; Yang, Chao-Chun; Plikus, Maksim V et al. (2015) CD133 expression correlates with membrane beta-catenin and E-cadherin loss from human hair follicle placodes during morphogenesis. J Invest Dermatol 135:45-55|
|Wong, Waihay J; Richardson, Theresa; Seykora, John T et al. (2015) Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J Invest Dermatol 135:454-461|
|Yang, Ruifeng; Zheng, Ying; Li, Ling et al. (2014) Direct conversion of mouse and human fibroblasts to functional melanocytes by defined factors. Nat Commun 5:5807|
|Thangapazham, Rajesh L; Klover, Peter; Wang, Ji-An et al. (2014) Dissociated human dermal papilla cells induce hair follicle neogenesis in grafted dermal-epidermal composites. J Invest Dermatol 134:538-540|
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