Regulation of stem cell (SC) activation and self-renewal is necessary for successful tissue development and homeostasis. In many tissues this is orchestrated by signals from supporting cells within the microenvironment called the SC niche. A thorough understanding of how mammalian SC niche cells become programmed and function during development to regulate SCs is a crucial requirement for future tissue-specific regenerative therapies. While much knowledge has been gained from studies in invertebrates, a molecular understanding of how niche cells in mammalian SC niches, such as the bone marrow, brain, intestine and hair follicles, acquire their specialized status is unknown due to the complexity of the tissues and the lack of methods to isolate and characterize the cells. We have recently developed novel genetic tools to study dermal papilla (DP) cells in the hair follicle SC niche, which are thought to direct follicular SC fate. We have purified these cells, defined their molecular identity and established assays to study their fate specification. This establishes a much needed mammalian model where formation and function of the SC niche can be studied. Our long- term goal is to understand the molecular mechanisms that govern SC niche fate specification, using hair follicle morphogenesis and regeneration as a model system. Our work has identified the molecular signature of DP cells, including a battery of signaling and transcription factors (TFs). In this proposal, we will test the hypothesis that the DP signature TFs contain the activity necessary and sufficient to regulate the SC activating, hair inducing DP niche fate. We will systematically manipulate signature TF expression in DP cells in vitro and in vivo to define the transcriptional control mechanisms that specify the molecular identity and functional activity of DP niche cells. We will further establish a novel inducible DP-specific in vivo gene targeting mouse model that is currently missing in the field. Finally, we will test with available mice that are targeted for conditional gene ablation, the necessity of candidate DP signature TFs for DP niche fate specification, using this novel in vivo gene ablation model, and in parallel with our established in vitro/in vivo hybrid knockout assay. Our work will identify the core transcriptional regulation of the SC niche fate of hair follicle DP cells. Activating the transcriptional program in isolated DP cells and in regular fibroblasts bears the promise to expand fully functional cells for therapeutic use in skin reconstructive efforts. These findings will have global relevance for other regenerative tissues, where SC niches operate to maintain tissue homeostasis, and potentially will lead to development of 3D-tissue regenerative therapies.

Public Health Relevance

A thorough understanding of the regulation of stem cell (SC) activation and self-renewal by supporting niche cells is a crucial requirement for future tissue-specific regenerative therapies. How the niche cells in mammalian SC niches acquire their specialized status is largely unknown. We will define the transcriptional control of niche fate specification of dermal papilla cells in the hair follicle SC niche, establishing a much needed mammalian model, where formation and function of the SC niche can be studied. Our work will improve our ability to create a more normal behaving skin tissue for future therapies and will also have global relevance for other regenerative tissues, where SC niches operate to maintain tissue homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059143-05
Application #
8625707
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2010-04-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$355,906
Indirect Cost
$144,226
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Rezza, Amélie; Sennett, Rachel; Rendl, Michael (2014) Adult stem cell niches: cellular and molecular components. Curr Top Dev Biol 107:333-72
Sennett, Rachel; Rezza, Amélie; Dauber, Katherine L et al. (2014) Cxcr4 is transiently expressed in both epithelial and mesenchymal compartments of nascent hair follicles but is not required for follicle formation. Exp Dermatol 23:748-50
Tsai, Su-Yi; Sennett, Rachel; Rezza, Amelie et al. (2014) Wnt/*-catenin signaling in dermal condensates is required for hair follicle formation. Dev Biol 385:179-88
Grisanti, Laura; Rezza, Amelie; Clavel, Carlos et al. (2013) Enpp2/Autotaxin in dermal papilla precursors is dispensable for hair follicle morphogenesis. J Invest Dermatol 133:2332-9
Grisanti, Laura; Clavel, Carlos; Cai, Xiaoqiang et al. (2013) Tbx18 targets dermal condensates for labeling, isolation, and gene ablation during embryonic hair follicle formation. J Invest Dermatol 133:344-53