Human amnion epithelial cells in the treatment of bronchopulmonary dysplasia
Creators: name: Vosdoganes, Patricia
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: There is a growing need for novel therapies to prevent and/or treat bronchopulmonary dysplasia (BPD). Cell-based therapies provide the potential to not only regulate lung inflammation and injury, but also support ongoing lung renewal and development. Of particular interest, human amnion epithelial cells (hAECs) prevent acute lung injury in adults and may provide a potential avenue for autologous cell therapy in infants with BPD. In that regard, this thesis aimed to determine if hAECs could prevent BPD-like injury in the fetal and neonatal lung. In my first study (Chapter 1), I have provided the first evidence that hAECs have the capacity to prevent BPD-like injury in fetal sheep following exposure to intrauterine inflammation, where hAEC treatment prevented alveolar simplification and changes to lung compliance induced by intra-amniotic injection of lipopolysaccharide (LPS). Lung repair was associated with a reduction in pulmonary inflammation but little evidence of hAEC engraftment. This supports a recent suggestion that the principal mechanism of hAEC-mediated lung repair is immune modulation, not regeneration of the pulmonary epithelium. Further, this study suggested that hAECs were most effective when delivered as a combination of both direct (intratracheal) and indirect (intravenous) therapy. Extending this result, I went on to demonstrate a similar capacity for lung repair when hAECs were administered to neonatal mice exposed to supplemental oxygen. In this study, hAEC treatment mitigated hyperoxia-induced changes to alveolar surface area and septation of the lung, reducing alveolar size and simplification. Structural improvements were again associated with a reduction in pulmonary inflammation, providing further evidence of their role as immune modulators in preventing BPD-like injury. Although the potential for hAECs to prevent acute lung injury was increasingly evident, their ability to repair established lung damage had not been demonstrated. As such, I performed a time-response study of hAEC therapy delivered to adult mice with established bleomycin-induced lung injury. I found that administration of hAECs normalised lung structure when administered at the peak stage of lung fibrosis – 14 days after bleomycin challenge. Interestingly, administration during peak inflammation – 7 days after bleomycin – had no effect on lung injury. This suggested that hAEC activity could be altered by mediators present within the pulmonary microenvironment relative to the timing of injury. In vitro studies failed to demonstrate a direct effect of hAECs on fibroblast proliferation or activity, suggesting that additional cell types/mediators were involved in the prevention of fibrosis in vivo. This study sheds new light on the possible mechanisms underpinning hAEC-mediated lung repair and ushers in future studies characterising the relationship between hAECs and the pulmonary immune response. This thesis has not only demonstrated for the first time a capacity for hAECs to prevent BPD-like lung injury, but has also shown that hAECs are capable of not only preventing acute lung damage, but also repairing established injury. This is paramount to the future use of hAECs in treating chronic lung diseases, including BPD. Further, questions raised in this thesis will guide future studies to focus on mechanisms of repair and to aid optimisation of hAEC therapy for clinical practice.