The global objective of this research is to elucidate the mechanisms underlying tissue homeostasis and regeneration in mammalian skin and to understand how this process goes awry in human disorders, including cancers. Central to achieving this goal is the purification and characterization of the differerent stem cell (SC) populations within skin and determination of their relative contributions to tissue homeostasis and wound- repair. Past AR050452 research led to purification of hair follicle (HF) bulge cells, and established them as self- renewing SCs that function in hair cycling and wound-repair. These HF-SCs also displayed more robust self- renewing and broader tissue regenerative potential than interfollicular epidermal (IFE)-SCs. Several differences might account for this. One is that like human IFE-SCs, mouse HF-SCs exist in a quiescent state for prolonged periods. Another is that they uniquely express transcription factors such as Nfatc1, which when absent, causes HF-SCs to lose quiescence and cycle HFs continuously. Past AR050452 research has set the foundations to tackle the following key questions: (1). Is HF-SC quiescence critical to their long-term maintenance? What happens when HFs cycle continuously? Do they expend their SCs over time? Can they heal wounds faster? (2) What are the molecular mechanisms governing the resting phase of the HF-SC niche? How does Nfatc1 and its associated transcriptional regulators function to maintain HF-SC quiescence? What are its direct targets and how do they regulate the balance between quiescence and long-term self-renewal? (3) What molecular changes define the difference between stemness and the transit amplifying state? Do stem cell progeny influence this transition and if so how?(4) What are the relative contributions of IFE and HF SCs to wound-repair? Does this differ in superficial vs deep wounds? In young vs adult mice? (5) How do IFE and HF SCs alter gene expression in response to injury? How fast are these changes and what controls the process? To answer these questions, we'll use FACS, RNA-seq, ChIP-seq, conditional gene knockout and RNAi screens in vivo and employ these methods to explore skin stem cells in their native, mutant and wound-induced environments.

Public Health Relevance

Stem cells are natural units of tissue repair and homeostasis, and their versatility holds promise for tissue regeneration. This research focuses on deciphering the properties of adult skin stem cells that exist within the epidermis and its appendages, in particular the hair follicles;specifically, we plan to focus on delineating the intrinsic mechaniss that render skin SCs their ability to self-renew in vitro and in vivo during normal homeostasis and in response to injury. This study is a fundamental prerequisite to ascertaining the potential of skin stem cells for regenerative therapies that go beyond burn treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR050452-11
Application #
8628335
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Baker, Carl
Project Start
2004-02-26
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Biology
Type
Graduate Schools
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
Lay, Kenneth; Kume, Tsutomu; Fuchs, Elaine (2016) FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential. Proc Natl Acad Sci U S A 113:E1506-15
Keyes, Brice E; Liu, Siqi; Asare, Amma et al. (2016) Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin. Cell 167:1323-1338.e14
Fuchs, Elaine (2016) Epithelial Skin Biology: Three Decades of Developmental Biology, a Hundred Questions Answered and a Thousand New Ones to Address. Curr Top Dev Biol 116:357-74
Fuchs, Elaine (2015) An unconventional route to becoming a cell biologist. Mol Biol Cell 26:3697-9
Fuchs, Elaine (2015) Cell biology: More than skin deep. J Cell Biol 209:629-31
Lu, Catherine; Fuchs, Elaine (2014) Sweat gland progenitors in development, homeostasis, and wound repair. Cold Spring Harb Perspect Med 4:
Hsu, Ya-Chieh; Li, Lishi; Fuchs, Elaine (2014) Emerging interactions between skin stem cells and their niches. Nat Med 20:847-56
Hsu, Ya-Chieh; Li, Lishi; Fuchs, Elaine (2014) Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157:935-49
Blanpain, Cédric; Fuchs, Elaine (2014) Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration. Science 344:1242281
Keyes, Brice E; Segal, Jeremy P; Heller, Evan et al. (2013) Nfatc1 orchestrates aging in hair follicle stem cells. Proc Natl Acad Sci U S A 110:E4950-9

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