Understanding how stem cells are regulated to promote tissue regeneration is key to developing targeted therapies to treat human diseases that lead to either tissue damage or uncontrolled growth in cancer. My research uses innovative technology to examine how a key stem cell molecular signals can recruit cells to undergo collective growth during normal tissue regeneration and how this mechanism can also be utilized aberrantly to promote cooperative growth during carcinogenesis.
Specialized Terms: Hair follicle stem cells; skin regeneration; wound healing
Tissue homeostasis and regeneration are mediated by the coordinated growth of multiple cell types to generate tissue that sustains integrity and function of the organism. This ability to durably regenerate tissue relies on adult stem cells that reside in a specialized environment called the niche, which influences their self-renewal, growth and differentiation. Failure to maintain or mobilize stem cells results in tissue loss and dysfunction, while uncontrolled activation of these cells can fuel disorganized growth and cancer. Elucidating how key molecular signals govern stem cell behavior holds tremendous implications for designing targeted therapies to treat human diseases. A major challenge to examining how mammalian stem cells are regulated is the inability of conventional static analysis to follow the fate and behavior of cell populations in vivo over time.
My research aims to uncover how heterotypic signals between the skin epidermis and dermis regulate robust and organized growth hair follicle growth during embryonic development and adult regeneration, as well as how dysregulation of these signals can result in skin cancer. In particular, my lab studies (1) how cellular behaviors such as cell divisions and movement are regulated by key morphogenetic signals during regeneration, (2) how these signals are spatially disseminated to a field of cells in to ensure robust but patterned and compartmentalized growth, and (3) how these mechanisms can contribute to disorganized and uncontrolled growth during tumorigenesis. The hair follicle is an ideal model to address these questions as it is exceptionally accessible and undergoes well-characterized growth and cyclical regeneration in a manner dependent on resident stem cells. By coupling this model to live imaging and single-cell genomic techniques we are uniquely poised to address these outstanding questions.
Specifically, I have examined how Wnt/β-catenin signaling, a key molecular pathway required for hair follicle regeneration, is propagated throughout a population of undifferentiated cells to promote synchronous and coordinated growth. By live imaging, we have found that only a subset of cells is required to fuel the non-cell autonomous activation of this signal and growth behaviors throughout surrounding epithelial cells and is associated with upregulation of diffusible Wnt ligands. One of my goals is to understand how cooperative epithelial growth coordinates normal hair follicle regeneration. The second is to examine how this mechanism of collective behavior regulates basal cell carcinomas (BCCs), the most common human skin cancer, which utilizes hair morphogenetic signals for growth. Third, I am interested in understanding how the mesenchyme regulates both organized regeneration and development and how we can apply this knowledge to modify tumor growth. Accomplishing these aims will provide novel insight into the principle mechanisms that ensure proper tissue regeneration and how they can also be exploited deleteriously to promote collective growth in cancer.
Dermatology; Epidermis; Homeostasis; Pathology; Regeneration; Stem Cells; Wound Healing; Carcinogenesis