Origin, fate, and function of embryonic Hic1-positive mesenchymal progenitors in the developing limb
department or school: Medicine, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Arostegui, Martin
issued: 2023-09-30T07:00:00Z
issued: 2022
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Tissue development and regeneration rely on the cooperation of multiple mesenchymal progenitor (MP) subpopulations. Recently, the gene Hypermethylated in cancer 1 ( Hic1) has been identified as a marker of quiescent MPs in multiple adult tissues. Hic1⁺ MPs have since been implicated in the repair and regeneration of several organs such as skeletal muscle (SkM), skin, heart, and brain. While the roles that Hic1⁺ MPs play in tissue maintenance are currently being elucidated, knowledge surrounding their developmental origin and fate is lacking. Using the developing forelimb as a model system, we describe the embryonic origin of Hic1⁺ MPs and demonstrate that they first appear in the developing limb ~48 hours after limb bud initiation at embryonic day (E) 11.5 and represent a rare subset of the total mesenchymal cell population. Time-resolved single cell-omics analyses coupled with lineage tracing reveal that Hic1⁺ cells generate a unique MP hierarchy, that includes both recently identified adult universal fibroblast populations (Dpt⁺, Pi16⁺ and Dpt⁺, Col15a1⁺) and more specialized mesenchymal derivatives such as, peri- and endo-neural cells, pericytes, bone marrow stromal cells (BMSCs), myotenocytes, tenocytes, and fascia-resident fibroblasts, with limited contributions to chondrocytes and osteocytes within the skeletal elements. We further demonstrate that, in the adult organism, MPs endure within these compartments, continue to express Hic1 and represent a critical reservoir to support post-natal growth and regeneration. Within the appendicular skeleton, Hic1⁺ descendants do not contribute to the primary skeletal anlagen but represent the elusive MP population that generate progeny which connect bone to tendon (entheses) and tendon to muscle (myotendinous junction). Furthermore, deletion of Hic1 leads to skeletal defects reflective of deficient muscle-bone coupling. Collectively, these findings demonstrate that Hic1 identifies a unique MP population that contributes …
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/82083
note: Origin, Fate, and Function of Embryonic Hic1-positive Mesenchymal Progenitors in the Developing Limb by Martin Arostegui B.Sc., The University of British Columbia, 2015 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Cell and Developmental Biology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2022 © Martin Arostegui, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Origin, Fate, and Function of Embryonic Hic1-positive Mesenchymal Progenitors in the Developing Limb submitted by Martin Arostegui in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cell and Developmental Biology Examining Committee: Michael Underhill, Professor, Cell and Developmental Biology, UBC Supervisor Timothy O’Connor, Professor, Cell and Developmental Biology, UBC Supervisory Committee Member Louis Lefebvre, Associate Professor, Medical Genetics, UBC University Examiner Francis Lynn, Associate Professor, Surgery, UBC University Examiner Additional Supervisory Committee Members: Douglas Allan, Associate Professor, Cell and Developmental Biology, UBC Supervisory Committee Member Pamela Hoodless, Professor, Medical Genetics, UBC Supervisory Committee Member iii Abstract Tissue development and regeneration rely on the cooperation of multiple mesenchymal progenitor (MP) subpopulations. Recently, the gene Hypermethylated in cancer 1 ( Hic1) has been identified as a marker of quiescent MPs in multiple adult tissues. Hic1+ MPs have since been implicated in the repair and regeneration of several organs such as skeletal muscle (SkM), skin, heart, and brain. While the roles that Hic1+ MPs play in tissue maintenance are currently being elucidated, knowledge surrounding their developmental origin and fate is lacking. Using the developing foreli…
has type: Thesis/Dissertation
date issued: 2022-11
is shown at: 10.14288/1.0415893
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
contributor: Underhill, T M
type: Text
identifier URI: http://hdl.handle.net/2429/82083