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

  • Author / Creator
    Stanislaus Alphonse, Anthuvan Rajesh
  • 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.

  • Subjects / Keywords
  • Graduation date
    Fall 2012
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Specialization
    • Medical Sciences - Paediatrics
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Stewart, Duncan (Department of Medicine)
    • Rossi, Fabio(Department of Medical Genetics)
    • Dr. John Greer (Department of Physiology)
    • Dyck, Jason (Department of Pediatrics)
    • Murray, Allan (Department of Medicine)