ERA

Download the full-sized PDF of Epithelial and vascular progenitors in the developing lung: Newer insights and therapeutic implicationsDownload the full-sized PDF

Analytics

Share

Permanent link (DOI): https://doi.org/10.7939/R3JG92

Download

Export to: EndNote  |  Zotero  |  Mendeley

Communities

This file is in the following communities:

Graduate Studies and Research, Faculty of

Collections

This file is in the following collections:

Theses and Dissertations

Epithelial and vascular progenitors in the developing lung: Newer insights and therapeutic implications Open Access

Descriptions

Other title
Subject/Keyword
Akt
ECFC
pulmonary hypertension
alveolar
endothelial colony forming cell
Lung
congenital diaphragmatic hernia
bronchopulmonary dysplasia
vascular progenitors
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Stanislaus Alphonse, Anthuvan Rajesh
Supervisor and department
Thebaud, Bernard (Department of Pediatrics)
Examining committee member and department
Dr. John Greer (Department of Physiology)
Dyck, Jason (Department of Pediatrics)
Stewart, Duncan (Department of Medicine)
Rossi, Fabio(Department of Medical Genetics)
Murray, Allan (Department of Medicine)
Department
Medical Sciences-Paediatrics
Specialization
Medical Sciences - Paediatrics
Date accepted
2012-05-16T15:41:50Z
Graduation date
2012-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Bronchopulmonary dysplasia (BPD) and congenital diaphragmatic hernia (CDH) are life-threatening lung diseases affecting newborn infants. Both diseases are characterized by impaired lung development and are currently untreatable. Dysregulation in the number or function of lung progenitor cells is one possible determinant of disrupted lung development. Stem cell augmentation is emerging as an appealing therapeutic strategy to promote lung growth. In fact, the integrated objective of the research presented in this thesis is to define the existence of resident progenitor cells in the distal lung and protect or supplement them to restore normal lung development. This objective is addressed using two approaches. The first approach involves enhancing the survival of alveolar type 2 (AT2) pneumocytes, which are considered the 'repair cells' of the lung alveoli and believed to harbour alveolar precursor cells. Excessive AT2 cell apoptosis impairs alveolar development and results in BPD in newborn rats exposed to hyperoxia (95% O2). Control of apoptosis in alveolar epithelial cells via overexpression of Akt (an intracellular prosurvival factor) protects hyperoxia-exposed rat pups from developing BPD. Our results constitute the framework for further therapeutic studies employing apoptosis control as a measure to prevent alveolar damage. The next approach derives partly from existing evidence that pro-angiogenic factors promote alveolar growth. Here, we explore the correspondingly likely role of vascular progenitors in lung growth and maintenance. We hypothesized that endothelial colony forming cells (ECFCs, recently recognized progenitors of the vascular endothelium) exist in the developing lung and impaired ECFC function underlies disrupted lung alveolar and vascular development. We found that ECFCs exist in the distal vasculature of developing human and rat lungs. Pulmonary vascular ECFCs isolated from newborn rats with hyperoxia-induced BPD or monocrotaline (MCT)-induced lung hypoplasia (simulating CDH-associated lung dysgenesis) expand less rapidly on culture, generate fewer colonies and form lesser vessel-like networks in Matrigel. Therapeutic supplementation with cord-blood ECFCs prevents BPD and restores alveolar structure in oxygen-exposed mice. ECFC treatment also attenuates MCT-induced PHT and preserves lung growth. Together, these observations suggest that ECFC supplementation represents a potential cell-based therapy for lung diseases characterized by impaired alveolar development. This research ushers in newer ideas that shall drive future research into evolving working remedies for BPD and CDH.
Language
English
DOI
doi:10.7939/R3JG92
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication

File Details

Date Uploaded
Date Modified
2014-05-01T03:07:37.018+00:00
Audit Status
Audits have not yet been run on this file.
Characterization
File format: pdf (Portable Document Format)
Mime type: application/pdf
File size: 16872252
Last modified: 2015:10:18 01:36:06-06:00
Filename: Stanislaus Alphonse_Anthuvan Rajesh_Fall 2012.pdf
Original checksum: 9626b11c091a96d265000f75ab5c4893
Well formed: true
Valid: false
Status message: Invalid Names dictionary offset=16869606
Status message: Invalid page tree node offset=16869606
Status message: Outlines contain recursive references.
File title: Rajesh-titlewith
Activity of users you follow
User Activity Date