The long term objective of this laboratory is to analyze the molecular and cellular mechanisms during development and regeneration of skin appendages. In the last funding periods, we made two major advances, each published in Nature. 1) Feathers have robust regenerative power, but the location of stem cells was unknown. We discovered feather stem cells are located in collar bulge. These stem cells are configured differently in radially and bilaterally symmetric feathers. The dermal papilla can set up the micro-environment within the follicle that builds stem cells into certain topological configurations. 2) The cycling of a single hair follicle has been studied, but the regenerative behavior of a population of hair follicles has not been studied. We found hair follicles form regenerative hair waves in the adult mouse, although hairs can also cycle simultaneously or randomly in other mammals. Analyses of the hair wave led us to discover a novel "dermal BMP clock" that modulates the progression of an internal hair cycle clock within each hair follicle. As a result, new functional phases of hair cycling stages are revealed: telogen can be further divided into "competent" and "refractory" phases, and anagen can be further divided into "propagating" and "autonomous" phases. The unexpected links of Bmp2 expression with subcutaneous adipocytes and the resetting of hair waves during pregnancy give implications in system biology. These studies revealed that stem cell activity is not only regulated by the niche, but also by hierarchical levels of the macro-environment. In the last version we hypothesize that skin appendage stem cell activity is regulated by both micro-environmental factors (defined here as compartments in the follicle, bulge niche, dermal papilla) and macro-environmental factors (defined here as environments outside of the follicle, surrounding dermis, neighboring follicles, systemic hormones, external environment). However, the proposal became too complex and reviewers recommended that we focus on just one of these two aims. Therefore, we now focus on the macro-environmental regulation of hair regeneration in living mammals. We further propose a new activator / inhibitor hypothetical model which suggests that cyclic dermal expression of multiple members of the BMP and Wnt pathways work together as activators and inhibitors to generate regenerative hair wave patterns. Different ratios of activator / inhibitor activity or duration of expression can lead to different lengths of autonomous / propagating anagen and refractory / competent telogen. This flexible model can accommodate physiological and pathological phenomena ranging from aging alopecia to seasonal molting. To test our hypothesis, we will continue to identify members with dermal cyclic expression, even though they have different rhythms. We will analyze hair wave patterns in genetically engineered mice. Transplantation of skin from transgenic mice to SCID mice will help us determine the molecular relationships involved in hair follicle-macro-environment interactions. Inter- dependence of hair follicles and subcutaneous adipocytes will be studied. We will also evaluate whether appendage stem cells can "sense" changes in the external environment. This novel concept has broad impact on skin biology, regeneration, and use of mouse skin for carcinogenesis or drug delivery. It also offers future promise to enhance or suppress hair growth via alteration of the macro-environment.

Public Health Relevance

Our previous work demonstrated that hair follicles cycle in coordinated waves. This means that they have the ability to communicate in some fashion. The nature of this communication remains unknown. Work proposed here will enable us to explore the role of the macro-environment (surrounding hair follicles;ie, the dermis, subcutaneous fat tissue, extracellular matrix) and external environment (photoperiod, temperature) in regulating the regenerative hair follicle waves. The work has practical significance in how to properly set environments for stem cells to make a new organ, as well as for those who use the mouse skin as a model for carcinogenesis study, drug delivery or stem cell research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042177-19
Application #
8464525
Study Section
Special Emphasis Panel (ZRG1-MOSS-H (02))
Program Officer
Baker, Carl
Project Start
1995-01-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
19
Fiscal Year
2013
Total Cost
$439,908
Indirect Cost
$168,360
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Ng, Chen Siang; Wu, Ping; Fan, Wen-Lang et al. (2014) Genomic organization, transcriptomic analysis, and functional characterization of avian ?- and ?-keratins in diverse feather forms. Genome Biol Evol 6:2258-73
Leung, Yvonne; Kandyba, Eve; Chen, Yi-Bu et al. (2014) Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration. Proc Natl Acad Sci U S A 111:15114-9
Chen, Chih-Chiang; Murray, Philip J; Jiang, Ting Xin et al. (2014) Regenerative hair waves in aging mice and extra-follicular modulators follistatin, dkk1, and sfrp4. J Invest Dermatol 134:2086-96
Wu, Ping; Alibardi, Lorenzo; Chuong, Cheng-Ming (2014) Regeneration of reptilian scales after wounding: neogenesis, regional difference, and molecular modules. Regeneration (Oxf) 1:15-26
Hughes, Michael W; Jiang, Ting-Xin; Lin, Sung-Jan et al. (2014) Disrupted ectodermal organ morphogenesis in mice with a conditional histone deacetylase 1, 2 deletion in the epidermis. J Invest Dermatol 134:24-32
Driskell, Ryan R; Jahoda, Colin A B; Chuong, Cheng-Ming et al. (2014) Defining dermal adipose tissue. Exp Dermatol 23:629-31
Chuong, Cheng-Ming; Yeh, Chao-Yuan; Jiang, Ting-Xin et al. (2013) Module-based complexity formation: periodic patterning in feathers and hairs. Wiley Interdiscip Rev Dev Biol 2:97-112
Li, Ang; Chen, Meng; Jiang, Ting-Xin et al. (2013) Shaping organs by a wingless-int/Notch/nonmuscle myosin module which orients feather bud elongation. Proc Natl Acad Sci U S A 110:E1452-61
Chueh, Shan-Chang; Lin, Sung-Jan; Chen, Chih-Chiang et al. (2013) Therapeutic strategy for hair regeneration: hair cycle activation, niche environment modulation, wound-induced follicle neogenesis, and stem cell engineering. Expert Opin Biol Ther 13:377-91
Wu, Ping; Wu, Xiaoshan; Jiang, Ting-Xin et al. (2013) Specialized stem cell niche enables repetitive renewal of alligator teeth. Proc Natl Acad Sci U S A 110:E2009-18

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