Mammalian skin and its appendages function as the outermost barrier of the body to protect inner organs from environmental hazards and keep essential fluids within the body. Homeostasis and integrity of mammalian skin are maintained by multiple progenitor and stem cell populations residing in distinct skin compartments. In particular, multipotent hair follicle stem cells (HFSCs) located in the bulge region maintain hair follicles (HFs) during normal hair cycle and epidermal wound healing. Understanding molecular mechanisms that regulate self-renewal and activation of HFSCs is a fundamental prerequisite to exploit these fascinating cells for regenerative medicine. Among the mechanisms, microRNAs (miRNAs) are a class of small, noncoding RNAs that take essential roles in mammalian gene regulation in diverse cell types and tissues. Unlike transcriptional mechanisms that potently activate or suppress gene expression, miRNAs regulate protein production of mRNAs at post-transcriptional levels and usually function to fine tune the output of the transcriptome. Despite modest regulation of individual targets, miRNAs broadly modulate a large number (60%) of genes and play important roles in a wide range of biological processes. In mammalian skin, the critical functions of the entire miRNA pathway in both embryonic skin development and maintenance of adult HF lineages have been well appreciated. In sharp contrast, there is no report identifying any individual miRNA that is required for the self-renewal of the HFSCs in adult skin. Consequently, the underlying mechanism of miRNA-mediated regulation in the HFSCs remains largely unknown. To address these important issues, we propose to focus on miR-205, the most highly expressed and functionally important miRNA in the HFSCs, and examine its roles in self- renewal and migration of adult HFSCs (Aim 1 and 2). To provide mechanistic insights for these functions, we will apply biochemical purification of miRISC and its associated mRNA targets to the WT and miR-205 knockout HFSCs and identify all miR-205-associated targets in an HFSC- specific manner. The long-term goal of this project is to elucidate individual miRNAs'functions and provide mechanistic insights to these molecules during homeostasis and stressed conditions including injury response and tumorigenesis in the HFSCs. Taken together, studies proposed here, if successful, will significantly enhance our knowledge about individual miRNAs'functions in adult HFSCs. The knowledge gained from these studies under normal and stressed conditions will pave the way to manipulate miRNAs and utilize these stem cells for regenerative medicine.

Public Health Relevance

Dynamic functions of hair follicle stem cells are governed by multiple mechanisms to maintain the stem cell population and to activate for hair follicle regeneration. In this proposal, I will investigate microRNA functions in self-renewal and migration of these stem cells with genetic mouse models. Knowledge gained from the proposed study will gain a mechanistic understanding of the stem cells for regenerative medicine and human skin diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR066703-01
Application #
8762616
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2014-07-01
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80303
Fan, Xiying; Wang, Dongmei; Burgmaier, Jeremy Evan et al. (2018) Single Cell and Open Chromatin Analysis Reveals Molecular Origin of Epidermal Cells of the Skin. Dev Cell 47:21-37.e5
Hoefert, Jaimee E; Bjerke, Glen A; Wang, Dongmei et al. (2018) The microRNA-200 family coordinately regulates cell adhesion and proliferation in hair morphogenesis. J Cell Biol 217:2185-2204
Yi, Rui (2018) The Skin(ny) on Regenerating the Largest Organ to Save a Patient's Life. Cell Stem Cell 22:14-15
Latil, Mathilde; Nassar, Dany; Beck, Benjamin et al. (2017) Cell-Type-Specific Chromatin States Differentially Prime Squamous Cell Carcinoma Tumor-Initiating Cells for Epithelial to Mesenchymal Transition. Cell Stem Cell 20:191-204.e5
Yi, Rui (2017) Concise Review: Mechanisms of Quiescent Hair Follicle Stem Cell Regulation. Stem Cells 35:2323-2330
Rezza, Amélie; Wang, Zichen; Sennett, Rachel et al. (2016) Signaling Networks among Stem Cell Precursors, Transit-Amplifying Progenitors, and their Niche in Developing Hair Follicles. Cell Rep 14:3001-18
Wang, Li; Siegenthaler, Julie A; Dowell, Robin D et al. (2016) Foxc1 reinforces quiescence in self-renewing hair follicle stem cells. Science 351:613-7
Bennett, Christopher G; Riemondy, Kent; Chapnick, Douglas A et al. (2016) Genome-wide analysis of Musashi-2 targets reveals novel functions in governing epithelial cell migration. Nucleic Acids Res 44:3788-800
Riemondy, Kent; Wang, Xiao-jing; Torchia, Enrique C et al. (2015) MicroRNA-203 represses selection and expansion of oncogenic Hras transformed tumor initiating cells. Elife 4: