Abstract
Cardiosphere-derived cells (CDCs) are a cardiac progenitor cell population, which have been shown to possess cardiac regenerative properties and can improve heart function in a variety of cardiac diseases. Studies in large animal models have predominantly focussed on using autologous cells for safety, however allogeneic cell banks would allow for a practical, cost-effective and efficient use in a clinical setting. The aim of this work was to determine the immunomodulatory status of these cells using CDCs and lymphocytes from 5 dogs. CDCs expressed MHC I but not MHC II molecules and in mixed lymphocyte reactions demonstrated a lack of lymphocyte proliferation in response to MHC-mismatched CDCs. Furthermore, MHC-mismatched CDCs suppressed lymphocyte proliferation and activation in response to Concanavalin A. Transwell experiments demonstrated that this was predominantly due to direct cell-cell contact in addition to soluble mediators whereby CDCs produced high levels of PGE2 under inflammatory conditions. This led to down-regulation of CD25 expression on lymphocytes via the EP4 receptor. Blocking prostaglandin synthesis restored both, proliferation and activation (measured via CD25 expression) of stimulated lymphocytes. We demonstrated for the first time in a large animal model that CDCs inhibit proliferation in allo-reactive lymphocytes and have potent immunosuppressive activity mediated via PGE2.
Highlights
Cardiac disease is a significant cause of death in humans, accounting for around 25% of all causes of mortality[1]
Layer of stromal like cells emerged from the atrial explants over which phase-bright cells proliferated (Fig. 1a). These cells formed spheres when plated on a low attachment surface (Fig. 1b), which were able to grow as a monolayer when re-plated on fibronectin-coated plastic to form Cardiosphere-derived cells (CDCs) (Fig. 1c)
Since our data indicated that a key mechanism in the potential induction of anergy in lymphocytes is the CDC-induced down-regulation of CD25, we explored the potential involvement of the prostaglandin pathway
Summary
Cardiac disease is a significant cause of death in humans, accounting for around 25% of all causes of mortality[1]. A phase 1 clinical trial in humans using autologous CDCs to treat myocardial infarction has demonstrated encouraging results[7,8] It has been shown in multiple models that CDCs provide beneficial effects to the heart post-injury, with early proposed mechanisms including direct differentiation and contribution to new myocardium[8,9,10]. Exploiting naturally occurring non-ischaemic myocardial diseases in dogs, which exhibit close analogy to an equivalent human condition, will act as an essential bridge between discoveries identified in rodent models and achievable clinical therapies. The development of a cellular treatment approach in dogs would have significant translational potential fostering advances in the human field This is relevant for non-ischaemic DCM where treatment options are limited to implantation of a left ventricular assist device as a bridge to transplantation. We investigate mechanisms in this interaction, using this in vitro canine model of transplant reactivity
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