Bratt, Jessica AJ (2019) Developing an alveolar model to test the regenerative potential of placental membrane mesenchymal stem cells in bronchopulmonary dysplasia. Doctoral thesis, Keele University.

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Abstract

Bronchopulmonary dysplasia (BPD) is a neonatal disease affecting the lungs of premature infants. Prematurely born infants have under-developed lungs and require invasive ventilation technologies to provide sufficient oxygen for survival. Artificial ventilation is thought to exacerbate BPD by causing mechanical and oxygen stress on the lung tissue. Despite improvements in paediatric respiratory management, BPD care is limited by a lack of appropriate treatment options and remains a key challenge for clinicians. The pathogenesis of BPD remains poorly understood and currently relies on animal models for investigation. This study looks at developing a hydrogel to provide a human relevant in vitro BPD model to investigate the potential regenerative capabilities of placenta mesenchymal stem cells as a cell-based therapy for BPD.
We successfully developed a collagen-elastin hydrogel representative of the human lung alveolus. This allows the co-culture of multiple lung cells in addition to an air-liquid interface which achieves hyperoxygen exposure (equivalent to clinical ventilation interventions) and allows assessment of output measures such as hydrogel contraction, imaging techniques and DNA quantification.
We identified a protocol to extract and expand cells from the tracheal suctions of ventilated infants. We cultured these cells within the previously developed model for assessment at hyperoxygen and compared cell function with human adult lung cells. We established that hyperoxygen had a detrimental effect on adult lung cell proliferation and the ability of cells to contract collagen-elastin hydrogels. Hyperoxygen had no observed effect on neonatal lung cells.
Finally, placenta derived MSCs (pMSCs) were isolated from the amnion and chorion membrane. We found hyperoxygen exposure has an adverse effect on the expression of MSC cell markers, cell proliferation and cell morphology. This could have implications when developing a cell therapy for the treatment of BPD. When co-cultured with adult lung fibroblast, pMSCs positively influenced the proliferation of adult lung fibroblasts through a paracrine mechanism. These results suggest that pMSCs have the potential to alleviate the oxygen stress that lung cells of BPD infants experience.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Bronchopulmonary dysplasia, neonatal lung, cell therapy, regenerative medicine, placenta mesenchymal stem cell, in vitro model, hyperoxygen
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Contributors: Wu, P (Thesis advisor)
Forsyth, NR (Thesis advisor)
El Haj, AJ (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 28 Nov 2019 09:06
Last Modified: 28 Nov 2019 09:40
URI: https://eprints.keele.ac.uk/id/eprint/7308

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