We are interested in elucidating the molecular mechanisms involved in tissue stem cell self-renewal and fate choice, in normal tissue development and homeostasis. Stem cells hold great promises for future therapies of numerous deadly diseases, yet their basic properties are not well understood. Progress in the field has been hampered by the difficulty of identifying tissue stem cells in the absence of specific biochemical markers. Increasing evidence suggested that stem cells are infrequently dividing cells, that could be identified in many mouse tissues as DMA label retaining cells (or LRCs). Recently we developed a strategy applicable to many self-regenerating tissues to pulse-label LRCs with the green fluorescent protein (GFP) fused to histone H2B. We have used the mouse skin and the hair follicle as model systems, since the relation between LRCs and skin epithelial stem cells had been investigated in most depth. In our preliminary work we tracked and isolated GFP LRCs and demonstrated that at least a fraction of these cells had a stem cell phenotype. In this proposal we describe in three Specific Aims strategies to examine in more detail the relation between LRCs and stem cells. We will: 1) classify LRCs into distinct sub- populations and investigate their sternness;2) examine their special cell cycle properties;3) characterize their distinct patterns of gene expression. To accomplish these goals we use in vivo cell tracking and in vitro cell sorting methods combined with a variety of assays which include: hair regeneration and skin wounding;cell culture and skin reconstitution;cell cycle kinetics;and microarrays. First, our data will have global relevance for the isolation and characterization of putative stem cells with LRCs properties from many tissues. Although we focus on the skin, our work will lead the way for similar approaches in many systems which lack the specific means to separate stem cells from other cells of their tissue of residence. Second, stem cell proliferation must be tightly controlled in tissues to regulate the balance between normal and abnormal growth. Our studies will unravel some of the mechanisms developed by putative SCs to control their proliferation, an important first step in understanding such perturbation in the diseased tissues. Finally, our work will provide some of the basic knowledge necessary for more efficient manipulation of skin stem cells for clinical applications such as cell transplantation on burn victims.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR053201-04S1
Application #
7847291
Study Section
Development - 1 Study Section (DEV)
Program Officer
Baker, Carl
Project Start
2009-06-10
Project End
2010-08-31
Budget Start
2009-06-10
Budget End
2010-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$81,312
Indirect Cost
Name
Cornell University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Wang, Alex B; Zhang, Ying V; Tumbar, Tudorita (2017) Gata6 promotes hair follicle progenitor cell renewal by genome maintenance during proliferation. EMBO J 36:61-78
Lee, Jayhun; Kang, Sangjo; Lilja, Karin C et al. (2016) Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis. Nat Commun 7:11278
Lee, Song Eun; Sada, Aiko; Zhang, Meng et al. (2014) High Runx1 levels promote a reversible, more-differentiated cell state in hair-follicle stem cells during quiescence. Cell Rep 6:499-513
Waghmare, Sanjeev K; Tumbar, Tudorita (2013) Adult hair follicle stem cells do not retain the older DNA strands in vivo during normal tissue homeostasis. Chromosome Res 21:203-12
Tumbar, Tudorita (2013) Knocking off their Sox: lineage-specific repression by Polycomb in epidermal stem cells. EMBO J 32:1970-1
Sada, Aiko; Tumbar, Tudorita (2013) New insights into mechanisms of stem cell daughter fate determination in regenerative tissues. Int Rev Cell Mol Biol 300:1-50
Lee, Jayhun; Hoi, Charlene S L; Lilja, Karin C et al. (2013) Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo. Proc Natl Acad Sci U S A 110:4634-9
Scheitz, Cornelia Johanna Franziska; Tumbar, Tudorita (2013) New insights into the role of Runx1 in epithelial stem cell biology and pathology. J Cell Biochem 114:985-93
Tumbar, Tudorita (2012) Ontogeny and Homeostasis of Adult Epithelial Skin Stem Cells. Stem Cell Rev :
Scheitz, Cornelia Johanna Franziska; Lee, Tae Seung; McDermitt, David James et al. (2012) Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J 31:4124-39

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