Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells in myocardial ischaemia/reperfusion injury

Lokman Dr, Adam Bin (2020). Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells in myocardial ischaemia/reperfusion injury. University of Birmingham. Ph.D.

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Abstract

Myocardial ischaemia/reperfusion (IR) injury is a major contributor to the clinical mortality and morbidity in patients who have suffered a myocardial infarction (MI). Although stem cell (SC)-based therapy for MI holds promise, clinical success has been poor. This may be due to a lack of knowledge of whether systemically infused SCs efficiently home and adhere within the injured heart and whether therapeutic mechanisms involve SCs conferring vasculoprotection in damaged coronary microvessels. Indeed, the microcirculatory perturbations that occur during myocardial IR injury itself are not well understood, as pre-clinical research has been incapable of routinely and reliably directly imaging the beating heart in vivo. This study has presented a novel technique for visualising these disturbances through the use of intravital microscopy (IVM) alongside ventricular blood flow assessment. Laser speckle contrast imaging (LSCI) showed a sustained hyperaemic ventricular response during reperfusion that was not transmitted downstream, as IVM of the coronary microcirculation showed heterogenic flow with patchy, disorganised reperfusion and reduced functional capillary density. This was accompanied by a thrombo-inflammatory response leading to aggregates of microthrombi that occluded coronary capillaries. There was a significant and rapid increase in adherent platelets, neutrophils and monocytes in the IR injured heart. HSC therapy produced a remarkable reverse in these phenomena in IR injured hearts, alleviating the thrombo-inflammatory response and restoring the microcirculation to an organised state. Surprisingly, this was achieved without the need for HSCs to home to the injured heart. This suggest an important paracrine role in HSC therapy that confers vasculoprotection to the microvessels of the heart, likely through a reduction in oxidative stress-induced endothelial cell damage, which was characterised by a reduction in levels of 8-OHdG (a marker for oxidative damage) and endothelial adhesion molecules (ICAM-1 & VCAM-1). This is also the first study to show the pro-inflammatory effects of topical application of IL-36 isoforms on the beating heart, with promising potential for the IL-36 receptor antagonist to reduce the inflammatory infiltration observed in IR injured hearts.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):