Continuous replacement and repair of adult epithelial tissues such as the skin, intestine, and lung depend on self-renewing stem cells which generate the specialized cells necessary for tissue maintenance. Recent work has shown that the local environment, or niche, in which stem cells reside is critical for their maintenance and function. Specifically, positioning of the stem cell within the niche exposes it to signals that promote its survival and maintenance and guide the production of specialized daughter cells that perform the normal tissue functions. Self-renewing cells that possess many normal stem cell properties have been identified in tumors, emphasizing that defining stem cell control mechanisms in normal tissues is important for understanding how stem cells contribute to cancer. Conversely, the idea of using stem cell therapeutics to treat diseases associated with stem cell loss, such as diabetes, and devastating injuries to tissues including the brain, spinal cord, or skin has generated enormous excitement. However, our lack of understanding of the mechanisms that regulate stem cells within their normal niches in vivo has hampered the advancement of these therapies for clinical applications. The goal of our proposed study is to understand how localized signals promote stem cell specification and maintenance within the niche. In mammals, like mice or humans, major technical challenges have made it difficult to identify adult stem cells within tissues, a problem that has prevented the identification of important signals that control stem cell behavior. Because of this, we are using the developing ovary in the fruit fly as a model system to directly examine epithelial stem cell regulation. Rapid progress has already been made in identifying components of the stem cell niche and specific genes that control stem cell behavior. Importantly, the genes identified so far also regulate stem cells in humans, suggesting that identifying new signals that control fly stem cell function will be broadly relevant. Using the fly ovary system, we recently found that integrins, a group of proteins that anchor cells in place, are important for maintaining epithelial Follicle Stem Cells (FSCs) within their niche. Without integrins, FSCs change shape, improperly divide and migrate, and lose their ability to function as stem cells. Similar defects are thought to contribute to cancer initiation, promotion, and progression in humans. Our data also demonstrates that FSCs produce a protein that is an important niche component. This novel finding suggests that many types of stem cells, perhaps including cancer stem cells, may have the capacity to initiate their own niche. The experiments proposed will define 1) how integrins participate in FSC regulation and 2) identify important genes and proteins that work together with integrins to control stem cell function. The outcome of these experiments will impact our understanding of epithelial stem cell function in general and also will have important implications for the development of techniques aimed at purifying stem cells for therapeutic use.

Public Health Relevance

Our present aim is to define epithelial stem cell control mechanisms in the fly ovary, where specific stem cell regulatory genes and their functions will be determined using genetics, live imaging, and developmental techniques. Defining stem cell control mechanisms in normal tissues is important for understanding how stem cells contribute to cancer and for developing stem cell therapeutics to treat developmental defects, traumatic injury, or diseases associated with stem cell loss, including diabetes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Intercellular Interactions (ICI)
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Ravindranath, Neelakanta
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Research Institute of Fox Chase Cancer Center
United States
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Hartman, Tiffiney R; Ventresca, Erin M; Hopkins, Anthony et al. (2015) Novel tools for genetic manipulation of follicle stem cells in the Drosophila ovary reveal an integrin-dependent transition from quiescence to proliferation. Genetics 199:935-57
Strochlic, Todd I; Stavrides, Kevin P; Thomas, Sam V et al. (2014) Ack kinase regulates CTP synthase filaments during Drosophila oogenesis. EMBO Rep 15:1184-91
Hartman, Tiffiney R; Strochlic, Todd I; Ji, Yingbiao et al. (2013) Diet controls Drosophila follicle stem cell proliferation via Hedgehog sequestration and release. J Cell Biol 201:741-57