The long-term goal of this project is to better understand the tissue microenvironment that controls the activity and behavior of epithelial stem cells. Epithelial stem cells are responsible for the maintenance and regeneration of self-renewing tissues such as epidermis, hair follicle, and mammary gland. We have begun analyzing the biology and function of subdermal adipocytes during skin tissue homeostasis. In mammals, depots of white adipose tissue store energy through lipid accumulation and can serve as paracrine signaling tissues. In the skin, subdermal adipocytes compose a unique adipose tissue depot that underlies the dermal fibroblasts and surrounds the hair follicle during hair growth. Data suggests that adipocytes may regulate hair follicle cycling and wounding, but the role of subdermal adipocytes in the skin is not known. Our preliminary data shows that subdermal adipocytes are essential for hair follicle cycling and wound healing and generate a dynamic microenvironment in the skin. We hypothesize that the interplay between skin cells and subdermal adipocytes is crucial for the regulation of epidermal homeostasis. To address this hypothesis, we will: 1. characterize whether subdermal adipocytes are important for maintaining the hair follicle stem cell phenotype by a. analyzing mice with genetic or pharmacologically induced defects in adipogenesis, resulting in defects in subdermal adipocytes and b. defining adipogenesis during the hair cycle. 2. determine if subdermal adipocytes play a role in epidermal wound healing by a. defining the wound healing response in mice with defects in subdermal adipocytes and b. defining the cellular mechanisms that lead to adipocyte regeneration during wound healing. 3. Define the molecular mechanisms by which subdermal adipocytes regulate skin homeostasis using in vitro assays with adipocytes to address the role of signaling molecule expression by these adipocytes in the skin. Patients with alopecia, hair shaft disorders, or chronic wounds could potentially benefit from this research.

Public Health Relevance

A thorough understanding of the regulation of epithelial stem cell behavior by the surrounding tissue environment is a crucial requirement for tissue-specific regenerative therapies to effectively treat human disease. The manner in which different cell types in mammalian tissues interact is largely unknown. We will define how a major but poorly understood cell type in the skin, subdermal adipocytes, act to control epidermal homeostasis and repair, establishing an essential mammalian model to study an intact tissue environment. Our work will improve our ability to create skin tissue for future therapies and will also have global relevance for other regenerative tissues, where adipocytes operate to maintain tissue homeostasis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AR060295-04
Application #
8654257
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Shook, Brett; Xiao, Eric; Kumamoto, Yosuke et al. (2016) CD301b+ Macrophages Are Essential for Effective Skin Wound Healing. J Invest Dermatol 136:1885-91
Rivera-Gonzalez, Guillermo C; Shook, Brett A; Andrae, Johanna et al. (2016) Skin Adipocyte Stem Cell Self-Renewal Is Regulated by a PDGFA/AKT-Signaling Axis. Cell Stem Cell 19:738-751
Shook, Brett; Rivera Gonzalez, Guillermo; Ebmeier, Sarah et al. (2016) The Role of Adipocytes in Tissue Regeneration and Stem Cell Niches. Annu Rev Cell Dev Biol 32:609-631
Goldstein, Jill; Roth, Eve; Roberts, Natalie et al. (2015) Loss of endogenous Nfatc1 reduces the rate of DMBA/TPA-induced skin tumorigenesis. Mol Biol Cell 26:3606-14
Alexander, Caroline M; Kasza, Ildiko; Yen, C-L Eric et al. (2015) Dermal white adipose tissue: a new component of the thermogenic response. J Lipid Res 56:2061-9
Rosowski, Kathryn A; Mertz, Aaron F; Norcross, Samuel et al. (2015) Edges of human embryonic stem cell colonies display distinct mechanical properties and differentiation potential. Sci Rep 5:14218
Stewart, Rachel M; Zubek, Amanda E; Rosowski, Kathryn A et al. (2015) Nuclear-cytoskeletal linkages facilitate cross talk between the nucleus and intercellular adhesions. J Cell Biol 209:403-18
Tadeu, Ana Mafalda Baptista; Lin, Samantha; Hou, Lin et al. (2015) Transcriptional profiling of ectoderm specification to keratinocyte fate in human embryonic stem cells. PLoS One 10:e0122493
Ebmeier, Sarah; Horsley, Valerie (2015) Origin of fibrosing cells in systemic sclerosis. Curr Opin Rheumatol 27:555-62
Roberts, Natalie; Horsley, Valerie (2014) Developing stratified epithelia: lessons from the epidermis and thymus. Wiley Interdiscip Rev Dev Biol 3:389-402

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