Pharmacological mobilisation of mesenchymal stem/ stromal cells (MSCs) for cardiac repair
File(s)
Author(s)
Todorova, Veneta Boyanova
Type
Thesis
Abstract
The healthcare burden of heart failure increases every year, and new therapies are in great demand. Mesenchymal stem/ stromal cell (MSC) transplantation is under investigation as a cell therapy for cardiac repair. Despite encouraging preclinical results, so far only modest effects on heart function were shown by clinical trials investigating this approach. It was suggested that the extensive culture expansion prior to transplantation is hindering the homing and reparative abilities of MSCs. To address this issue, I propose the use of a pharmacological approach to harness the therapeutic potential of MSCs. I hypothesised that increasing MSC mobilisation after MI using drugs could improve cardiac repair. To investigate this, I first showed that endogenous MSCs mobilise into the circulation on day 5 after myocardial infarction (MI) in the rat. This mobilisation was further increased using a combination of two FDA approved drugs: a 5-day pre-treatment using mirabegron (β3-adrenergic receptor agonist), followed by a single dose of AMD3100 (CXCR4 antagonist) (MA). Given in the first 5 days after MI, this therapy resulted in improved global heart function at 5 weeks post injury as shown by our blinded cardiac MRI analysis: increased left ventricular ejection fraction and cardiac output, and decreased end systolic volume. Histological analysis revealed that the MA treated rats had decreased cardiac interstitial fibrosis and increased vascularisation in the border zone of the infarct. Plasma levels of IL-6, TNF-α, and anti-cardiac troponin I autoantibodies were decreased in the MA treated group at 5 weeks post MI. In vitro experiments showed that conditioned media from blood derived MSCs can support angiogenesis in the context of endothelial tube formation and wound healing assays, and that IL-6 and TNF-α decrease the force of contraction in a myocardial slice model. Based on these findings, I propose a novel pharmacological cell therapy for cardiac repair.
Version
Open Access
Date Issued
2022-05
Date Awarded
2022-08
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Rankin, Sara
Harding, Sian
Sponsor
British Heart Foundation
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)