Tissue homeostasis and regeneration are sustained by stem cells, which are cells able to both replenish their own progenitor cell pool as well as give rise to differentiated cells throughout the life of a tissue. The environment in which stem cells reside, the so-called niche, regulate their special abilities. Stem cell regulation is key fo tissue function. Failure to properly activate stem cells will hinder tissue repair and lead to orga failure, while improper stem cell activation will lead to overgrowth and cancer. Therefore, the basic elucidated in researching stem cells and their niches may be invaluable in moving towards cures for a range of diseases. We still lack critical knowledge of the dynamic mechanisms of stem cell regulation. One of the major obstacles to gaining that knowledge is lack of access to a well-defined niche in which the discrete steps of regeneration can be observed and manipulated. The goal of my laboratory research is to understand the cellular and signaling mechanisms that govern stem cells and what goes awry in a disease state. To understand these fundamental principles of stem cell biology, we make use of the unique mammalian stem cell niche within the skin hair follicle because of its exceptional accessibility and well-defined structure. My laboratory has established an in vivo strategy to visualize the components of the hair follicle stem cell niche, in order to manipulate them and to ask specifically which signals, when disrupted, give rise to disease. Using a novel, non-invasive, two-photon imaging approach we follow the stem cell niche of the hair follicle in real-time in live mice. By these means, we have studied the behavior of the epithelial stem cells and their progeny during physiological hair regeneration and how the mesenchymal niche influences their behavior. The goal of this proposal is to use an integrated approach of cutting edge imaging technology, genetic manipulation and cell biology to advance our understanding of the mechanisms that activate stem cells and sustain tissue regeneration. These experiments will be key to reveal the dynamics of stem cell niche components in vivo in real time. Given that niche components and signaling have been shown to be conserved in other organs, our findings about the fundamental principles that govern stem cells will likely be relevant to other tissues, and will advance therapeutic strategies for the cure of diseases.

Public Health Relevance

Research into stem cell holds tremendous promise to cure disease. The proposed research will utilize novel strategies that will enable us to capture aspects of biology heretofore inaccessible, and that will have broad implications for understanding mechanisms that govern stem cells during normal regeneration and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR063663-01
Application #
8416828
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Baker, Carl
Project Start
2012-09-07
Project End
2017-08-31
Budget Start
2012-09-07
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$373,688
Indirect Cost
$148,688
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Park, Sangbum; Greco, Valentina; Cockburn, Katie (2016) Live imaging of stem cells: answering old questions and raising new ones. Curr Opin Cell Biol 43:30-37
Sun, Thomas Yang; Haberman, Ann M; Greco, Valentina (2016) Preclinical Advances with Multiphoton Microscopy in Live Imaging of Skin Cancers. J Invest Dermatol :
Xin, Tianchi; Greco, Valentina; Myung, Peggy (2016) Hardwiring Stem Cell Communication through Tissue Structure. Cell 164:1212-25
Rompolas, Panteleimon; Mesa, Kailin R; Kawaguchi, Kyogo et al. (2016) Spatiotemporal coordination of stem cell commitment during epidermal homeostasis. Science 352:1471-4
Pineda, Cristiana M; Park, Sangbum; Mesa, Kailin R et al. (2015) Intravital imaging of hair follicle regeneration in the mouse. Nat Protoc 10:1116-30
Mesa, Kailin R; Rompolas, Panteleimon; Zito, Giovanni et al. (2015) Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool. Nature 522:94-7
Mesa, Kailin R; Rompolas, Panteleimon; Greco, Valentina (2015) The Dynamic Duo: Niche/Stem Cell Interdependency. Stem Cell Reports 4:961-6
Greco, Valentina; Sedwick, Caitlin (2014) Valentina Greco: Got hair? J Cell Biol 207:436-7
Rompolas, Panteleimon; Greco, Valentina (2014) Stem cell dynamics in the hair follicle niche. Semin Cell Dev Biol 25-26:34-42
Zito, Giovanni; Saotome, Ichiko; Liu, Zongzhi et al. (2014) Spontaneous tumour regression in keratoacanthomas is driven by Wnt/retinoic acid signalling cross-talk. Nat Commun 5:3543

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