Elucidation of the fate and function of mesenchymal progenitors in tissue renewal and regeneration
department or school: Medicine, Faculty of
department or school: Cellular and Physiological Sciences, Department of
data provider: DSpace
degree campus: UBCV
creator: Scott, Wilder
issued: 2020-05-31T07:00:00Z
issued: 2019
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Adult tissues contain multiple stem and progenitor cells that are critical for their renewal and regeneration. Tissue resident stem/progenitor populations include mesenchymal progenitors (MPs) whose function and fate are unclear. These studies have been hampered by the lack of suitable solitary markers of these cells which would enable both lineage tracing and functional analyses of MPs. Using a discovery-based approach, the gene Hypermethylated in cancer 1 (Hic1) has been identified as such a marker. Subsequently, two novel knock-in alleles of Hic1 were generated and characterized as part of this project and these analyses showed that Hic1 is restricted to quiescent MPs in muscle and other tissues. Single cell RNA-seq was employed to examine Hic1⁺ cells in muscle and this led to the identification of 3 predominant MP subpopulations with distinct function(s) and lineage potential. Further analysis in muscle injury models revealed that these cells exhibit diverse stage-specific activities, which coordinate multiple aspects of the regenerative process. Following regeneration, Hic1⁺ progeny contribute to several mesenchymal derivatives including Col22a1-expressing cells in the myotendinous junction. In numerous tissues, MPs have been found to play a vital role in stem cell niches. Single cell-seq was employed to characterize MPs across tissues, and these analyses revealed extensive intra and inter-tissue heterogeneity. Within some tissues, unique populations could be identified that appeared based on gene expression to have niche-like properties. This was very evident in the populations characterized from bone marrow (BM), which contribute to the hematopoietic stem cell (HSC) niche. Deletion of Hic1 led to widespread MP hyperplasia, including in the BM. Interestingly, this led to a 2-fold increase in HSC number. Taken together, these results suggest that the Hic1⁺ MPs contribute to the HSC niche and that MP frequency regulates HSC niche capacity. In summary, these find…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/68994
note: ELUCIDATION OF THE FATE AND FUNCTION OF MESENCHYMAL PROGENITORS IN TISSUE RENEWAL AND REGENERATION by Wilder Scott BSc (Hons), The University of Saskatchewan, 2006 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Cellular and Physiological Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) March 2019 © Wilder Scott, 2019 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Elucidation of the fate and function of mesenchymal progenitors in tissue renewal and regeneration. submitted by Wilder Scott in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cell and developmental biology Examining Committee: T. Michael Underhill Supervisor Tim O’Connor Supervisory Committee Member Kelly McNagny Supervisory Committee Member Francis Lynn University Examiner Edward Conway University Examiner Additional Supervisory Committee Members: Fabio Rossi Supervisory Committee Member Supervisory Committee Member iii Abstract Adult tissues contain multiple stem and progenitor cells that are critical for their renewal and regeneration. Tissue resident stem/progenitor populations include mesenchymal progenitors (MPs) whose function and fate are unclear. These studies have been hampered by the lack of suitable solitary markers of these cells which would enable both lineage tracing and functional analyses of MPs. Using a discovery-based approach, the gene Hypermethylated in cancer 1 (Hic1) has been identified as such a marker. Subsequently, two novel knock-in alleles of Hic1 were generated and characterized as part of this project and these analyses showed that Hic1 is restricted to quiescent MPs in muscle and other tissues. Single cell RNA-seq was employed to examine Hic1+ cells in muscle and this led to the identification of 3 predominant …
has type: Thesis/Dissertation
date issued: 2019-05
is shown at: 10.14288/1.0377224
language: eng
degree discipline: Cell and Developmental Biology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/68994