Tissue homeostasis and regeneration are sustained by stem cells, which must both continually renew themselves while keeping up with the demand of new differentiated cell types to replace those lost throughout the life of a tissue. Failure to properly balance these two processes can lead to a host of problems, including impaired organ function and tissue repair, as well as tissue overgrowth and cancer. Understanding the basic mechanisms underlying this delicate equilibrium of stem cell self-renewal and differentiation is an essential step in preventing and treating a wide range of diseases. We still lack fundamental knowledge of how these stem cell behaviors are regulated during tissue regeneration in an intact, living tissue. The goal of this proposal is to understand how individual stem cell decisions are made within the stem cell population so that collectively their behaviors remain balanced within the broader context of the tissue, while preserving both structure and function. The challenge in addressing these fundamental questions lies in the inability to study these dynamic cellular processes in an intact mammal. To this end, my laboratory has established an in vivo strategy to directly visualize and manipulate stem cells in the skin epithelium of live mice, taking advantage of its unique accessibility, continuous regeneration throughout its lifetime, and the presence of multiple stem cell populations that use distinct regenerative strategies. Using a novel, non-invasive two-photon imaging approach, we are finally able to follow stem cells as they self-renew and differentiate over time. In order to understand how stem cell behaviors are balanced , and determine how a stem cell's shape, position and molecular character affect cell fate decisions and the overall regenerative ability of the tissue, we have combined our imaging approach with newly developed methods that allow us to manipulate each cell and their behavior individually in a live mouse. This unique combination of expertise, knowledge, and development of novel in vivo imaging tools has allowed us to first, define aspects of tissue regeneration that were previously inaccessible, revealing unexpected principles of stem cells and second, to understand the complex interplay between stem cell behaviors that fuel tissue regeneration over time. The goal of this proposal is to advance our understanding of how stem cell behaviors are balanced to sustain tissue regeneration over time through the use of an integrated approach of cutting edge imaging technology, genetic manipulation and cell biology. Given that many aspects of stem cell biology have been shown to be widely conserved in other organs, our findings will be relevant to other tissues as well, and will provide an important foundation for the treatment of a range 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 #
2R01AR063663-06A1
Application #
9522616
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Tseng, Hung H
Project Start
2012-09-07
Project End
2023-02-28
Budget Start
2018-04-01
Budget End
2019-02-28
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Mesa, Kailin R; Kawaguchi, Kyogo; Cockburn, Katie et al. (2018) Homeostatic Epidermal Stem Cell Self-Renewal Is Driven by Local Differentiation. Cell Stem Cell 23:677-686.e4
Xin, Tianchi; Gonzalez, David; Rompolas, Panteleimon et al. (2018) Flexible fate determination ensures robust differentiation in the hair follicle. Nat Cell Biol 20:1361-1369
Park, Sangbum; Gonzalez, David G; Guirao, Boris et al. (2017) Tissue-scale coordination of cellular behaviour promotes epidermal wound repair in live mice. Nat Cell Biol 19:155-163
Burclaff, Joseph; Mills, Jason C (2017) Cell biology: Healthy skin rejects cancer. Nature 548:289-290
Brown, Samara; Pineda, Cristiana M; Xin, Tianchi et al. (2017) Correction of aberrant growth preserves tissue homeostasis. Nature 548:334-337
Sun, Thomas Yang; Haberman, Ann M; Greco, Valentina (2017) Preclinical Advances with Multiphoton Microscopy in Live Imaging of Skin Cancers. J Invest Dermatol 137:282-287
Xin, Tianchi; Greco, Valentina; Myung, Peggy (2016) Hardwiring Stem Cell Communication through Tissue Structure. Cell 164:1212-1225
Rompolas, Panteleimon; Mesa, Kailin R; Kawaguchi, Kyogo et al. (2016) Spatiotemporal coordination of stem cell commitment during epidermal homeostasis. Science 352:1471-4
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
Mesa, Kailin R; Rompolas, Panteleimon; Greco, Valentina (2015) The Dynamic Duo: Niche/Stem Cell Interdependency. Stem Cell Reports 4:961-6

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