Abnormalities of skin melanocytes (Mcs) can cause a number of skin pigmentation diseases including hyper/hypo skin pigmentation, as well as the most aggressive form of skin cancer, melanoma, that still lacks a cure. One of the major obstacles in developing effective treatments for melanoma as well as many other pigmentary disorders is our poor understanding of the organization and regulation of Mc stem cells (McSCs). Thus far, McSCs have been only identified in the hair follicle, and it is not known whether McSCs are present in the skin epidermis. Moreover, little is known about how McSCs are molecularly regulated. This is in stark contrast to epithelial stem cells whose identity and characterization have been key to interrogating this population and determining how epithelial stem cells are regulated during tissue regeneration as well as during carcinogenesis. During the last granting period, we made two important discoveries: First, we found that Wnt signaling regulates the self-renewal and differentiation of McSCs as well as their melanoma-transformation in an established melanoma mouse model. Second, we found that a subpopulation of Mcs in the epidermis also displays active Wnt signaling, and these epidermal Mcs persist for long-term within the epidermis. We hypothesize that Wnt-active epidermal Mcs represent a McSC population that maintains and regenerates Mcs in the skin epidermis and can transform into melanoma cells. We will test this hypothesis in three Specific Aims.
Under Aim1, we will perform in vivo genetic lineage analysis under normal homeostasis and during Mc proliferation following UV exposure in parallel with ex vivo skin/hair reconstitution assays to determine whether Wnt-active epidermal Mcs self-renew and differentiate to durably maintain epidermal or hair Mcs.
Under Aim 2, we will examine how Wnt signaling regulates the behavior of epidermal Mcs under normal homeostasis and following UV exposure. For this, we will perform Wnt loss- and gain-of-function experiments in Mcs employing established genetic mouse models.
Under Aim3, we will test the ability of epidermal Mcs to form melanoma upon expression of melanoma-inducing mutations in a transplantation model. In summary, this study will be the first to definitively address the presence of McSCs within the skin epidermis and to begin to define how epidermal McSCs are regulated. Our findings will have a major impact in the field of Mc and melanoma biology. Newly identified McSCs within the skin epidermis and the Wnt pathway that regulates their behavior will provide novel targets for the prevention and treatment of melanoma as well as various pigmentation diseases.

Public Health Relevance

Pigmentation diseases including melanoma arise from epidermal melanocytes in which McSC population has not been identified. We will address the presence of McSCs within the skin epidermis and begin to define how Wnt signal regulates epidermal melanocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR059768-08S1
Application #
9734379
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tseng, Hung H
Project Start
2011-08-05
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Dermatology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Sun, Qi; Rabbani, Piul; Takeo, Makoto et al. (2018) Dissecting Wnt Signaling for Melanocyte Regulation during Wound Healing. J Invest Dermatol 138:1591-1600
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
Takeo, Makoto; Lee, Wendy; Rabbani, Piul et al. (2016) EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling. Cell Rep 15:1291-302
Takeo, Makoto; Lee, Wendy; Ito, Mayumi (2015) Wound healing and skin regeneration. Cold Spring Harb Perspect Med 5:a023267
Takeo, Makoto; Chou, Wei Chin; Sun, Qi et al. (2013) Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature 499:228-32
Chou, Wei Chin; Takeo, Makoto; Rabbani, Piul et al. (2013) Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling. Nat Med 19:924-9
Myung, Peggy S; Takeo, Makoto; Ito, Mayumi et al. (2013) Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration. J Invest Dermatol 133:31-41
Myung, Peggy; Ito, Mayumi (2012) Dissecting the bulge in hair regeneration. J Clin Invest 122:448-54
Rabbani, Piul; Takeo, Makoto; Chou, WeiChin et al. (2011) Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell 145:941-955