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UC Merced UC Merced Electronic Theses and Dissertations UC Merced UC Merced Electronic Theses and Dissertations Title REGULATION OF STEM CELL FUNCTION IN THE ADULT BODY Permalink https://escholarship.org/uc/item/44r5x132 Author Peiris, Tanuja Harshani Publication Date 2014 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California REGULATION OF STEM CELL FUNCTION IN THE ADULT BODY By: Tanuja Harshani Peiris DISSERTATION Submitted in satisfaction of the requirements for the degree of DOCTORATE OF PHILOSOPHY in Quantitative Systems Biology With an emphasis in Stem cell biology, Tissue repair and Regeneration in the OFFICE OF GRADUATE STUDIES of the UNIVERSITY OF CALIFORNIA, MERCED Committee Advised: Dr. Nestor Oviedo Dr. Jennifer Manilay Dr. David Ojcius Dr. Ricardo Zayas 2014 Copyright Tanuja Harshani Peiris, 2014. All rights reserved. ii Signature page The dissertation of Tanuja Harshani Peiris is approved by, and is accepted in the quality and form for publication on microfilm and electronically: _____________________________________ Dr. Jennifer Manilay (Chair) ____________________________________ Dr. Nestor Oviedo (Advisor) _____________________________________ Dr. David Ojcius _____________________________________ Dr, Ricardo Zayas iii Dedication In dedication to my mother for her love and support and for always been therefore me. A special feeling of gratitude also to my father and sister for all the help and encouragement. iv Table of Contents Figure and Tables ........................................................................................................................ xii Acknowledgements ...................................................................................................................... xv Curriculum vitae ......................................................................................................................... xvii Abstract ....................................................................................................................................... xxix Chapter 1 ........................................................................................................................................ 1 Stem Cells and their implications towards, cancer initiation, tissue repair and regeneration 1 1.1 – Introduction ....................................................................................................................... 1 Stem cells and history .............................................................................................................. 1 1.2 - Stem Cell characterization ................................................................................................. 2 1.3 - Stem cell division theory ..................................................................................................... 3 1.4 - Stem cells and cancer ......................................................................................................... 4 1.5 - How do stem cells maintain wound repair and regeneration? ......................................... 5 1.6 - Stem Cells and maintenance of tissue homeostasis ........................................................... 6 Chapter 2 ........................................................................................................................................ 8 Planaria as a model organism to study in vivo stem cell regulation .......................................... 8 2.1 – Planaria as a model organism ........................................................................................... 8 2.2 - Planaria Classification and physiology .......................................................................... 10 Chapter 3 ...................................................................................................................................... 13 Materials and Methods ................................................................................................................ 13 Identification of homologs and Phylogenetic analysis .......................................................... 13 Planarian Culture ....................................................................................................................... 13 Cloning ...................................................................................................................................... 13 dsRNA synthesis ....................................................................................................................... 14 Riboprobe synthesis ................................................................................................................. 14 Microinjections .......................................................................................................................... 15 In vitro dsRNA synthesis ......................................................................................................... 15 RNAi by feeding ....................................................................................................................... 15 v Whole mount Immunofluoresence .......................................................................................... 15 Brdu Staining ........................................................................................................................... 16 Planaria Dissociation and cell collection .................................................................................. 16 Fixation of dissociated cells ...................................................................................................... 16 Protein extraction ..................................................................................................................... 17 Western Blot .............................................................................................................................. 17 Flow Cytometry analysis ........................................................................................................... 17 TUNEL Assay .............................................................................................................................. 18 Measurements of planaria and image processing ................................................................. 18 RNA Extraction ........................................................................................................................ 19 cDNA synthesis ......................................................................................................................... 19 Quantitative RT-PCR .............................................................................................................. 19 In situ hybridization (ISH) ...................................................................................................... 19 Comet Assay ............................................................................................................................. 19 Karyotyping Assay ................................................................................................................... 20 Oligonucleotides ....................................................................................................................... 20 Oligos Used for cloning .......................................................................................................... 20 Oligos used for qpcr ............................................................................................................... 21 Chapter 4 ...................................................................................................................................... 22 TOR signaling regulates planarian stem cells and controls localized and organismal growth ....................................................................................................................................................... 22 4.1 - Introduction ..................................................................................................................... 22 4.1.1 - Target of Rapamycin Structure ................................................................................... 22 4.1.2 - Target of Rapamycin functions ................................................................................... 25 4.1.3 – PTEN in smed .............................................................................................................. 26 4.2 Results ................................................................................................................................. 27 4.2.1 - Identification of smed-TOR and TOR pathway homologs ........................................... 27 4.2.2 - TOR is ubiquitously expressed in planaria ................................................................... 29 4.2.3 - Planarian TOR is down regulated upon RNAi ............................................................. 30 4.2.4 - TOR is important for cell proliferation and growth .................................................... 32 4.2.5 - TOR (RNAi) inhibits systemic neoblast and successive progeny populations .............. 34 vi 4.2.6 - TOR(RNAi) increases cell death ................................................................................... 36 4.2.7 - TOR is essential for organismal growth and long term tissue maintenance .............. 37 4.2.8 - TOR signaling is required for blastema formation and cell proliferation post amputation ...........................................................................................................................
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