AbstractBritish Lung Foundation research estimates that lung disease affects almost one fifth of the UK population and is one of the UK’s three biggest killers alongside cardiovascular disease and non-respiratory cancers. Unfortunately, as chronic respiratory diseases progress, the efficacy of supportive treatments tends to decline. Mesenchymal stem cell (MSC) therapies offer a novel approach due to the immunomodulatory and reparative/regenerative properties of these cells. So, while the bulk of current respiratory disease treatments are aimed at managing symptoms and delaying disease progression, MSC therapies have the potential to promote pulmonary repair/regeneration and restore lung function. Therefore, the Scnn1b-transgenic (Tg) overexpression mouse model of chronic inflammatory lung disease was used to assess the therapeutic potential of MSCs and their secretome in a whole-body approach.
MSC-based therapy significantly reduced inflammation and lung damage, with a concomitant improvement in pulmonary function in Scnn1b-Tg mice. Subsequently, administration of the MSC secretome, in a complementary cell-free approach, was investigated to see if similar effects could be achieved. Scnn1b-Tg mice were subcutaneously injected or intranasally instilled with control media or MSC-conditioned media (MSC-CM) for two weeks, after which they were sacrificed at postnatal day 14 (prophylactic) or 6 weeks of age (therapeutic). Analysis of the bronchoalveolar lavage fluid revealed significantly reduced neutrophilia in Scnn1b-Tg mice systemically treated with MSC-CM. Histological and pulmonary function analyses revealed that prophylactic, but not therapeutic, MSC-CM administration significantly reduced lung damage in Scnn1b-Tg mice. Overall, these findings highlight the potential of MSCs and their secretome to limit lung damage and/or promote pulmonary repair/regeneration in the Scnn1b-Tg mouse model of chronic lung disease.
Given that MSC-CM significantly restored peroxisome proliferator-activated receptor γ (PPARγ) nuclear localisation and enhanced the phosphorylated levels of adenosine monophosphate-activated protein kinase (AMPK) in the distal conducting airway epithelia of 2-week-old Scnn1b-Tg mice, PPARγ induction and AMPK activation studies were conducted to investigate the underlying mechanisms of action. The results suggest that while the MSC secretome appears to exert its immunomodulatory effects, at least in part, through PPARγ induction, it primarily affects its changes through AMPK activation.
Thesis embargoed until 31 July 2027.
|Date of Award||Jul 2022|
|Supervisor||Sinead Weldon (Supervisor), Anna Krasnodembskaya (Supervisor), Cliff Taggart (Supervisor) & Declan Doherty (Supervisor)|
- Mesenchymal stem/stromal cell
- MSC secretome
- respiratory medicine
- pulmonary repair/regeneration
- chronic lung disease
- chronic obstructive pulmonary disease
- cystic fibrosis
- Scnn1b-transgenic mouse model
- beta ENaC mice