ÌÇÐÄvlogÊÓƵ

The interactions between mesenchymal and cardiac stem cells in the management of dilated cardiomyopathy

Supervisors: Dr Jayesh Dudhia (jdudhia@rvc.ac.uk), Dr David Connolly (dconnolly@rvc.ac.uk) and Dr Brian Catchpole

Background: The purpose of this exciting unique and novel PhD programme is to ascertain to what extent the communication between mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs), necessary for normal cardiac function, is disrupted in dog breeds predisposed to primary dilated cardiomyopathy (DCM) and how this disruption results in the progressive loss of systolic function and cardiac dilation. This would inform potential new therapies based either on drug therapy or allogeneic transfer of MSCs from breeds not susceptible to DCM into affected dogs to restore cardiac function. DCM is a common disease in dogs which leads to signs of congestive heart failure, arrhythmogenesis and often sudden death. The cumulative prevalence of cardiomyopathy in European Doberman pinchers is as high as 44% in dogs aged > 8 years and presents major welfare and economic concerns with medical management consisting of standard treatment for congestive heart failure and severe arrhythmia (Wess et al 2010). In this breed the disease is particularly aggressive with a high incidence of sudden death or refractory heart failure despite medication. The limited response to standard treatment in these dogs and in the phenotypically similar human disease demonstrates the need to develop better therapies for this devastating condition. Recent new findings in a model of ischemic heart disease show that the communication between MSCs and CSCs is a fundamental requisite for driving repair of cardiac tissue (Hatzistergos et al 2010). This work showed that MSCs could drive the proliferation and subsequent differentiation of endogenous CSCs into cardiomyocytes leading to repair. It is therefore likely that in non-ischemic myocardial disease similar cellular interactions will play an essential role in reverse remodelling of the damaged myocardium.

Historically, autologous MSC transfer predominated because of concern regarding immune rejection if cells from non-related individuals were used. However, it appears that MSCs are “immuno-privileged” and as such do not seem to trigger an allogeneic response by the host immune system (Massimo et al 2002) and a number of protective mechanisms have been identified (Le Blanca et al 2003, Amado et al 2005, Henry et al 2009). Allogeneic cell transfer in a proof of concept study has been demonstrated in porcine and canine models of myocardial infarction (MI) (Hatzistergos et al 2010, Vela et al 2009) and a recent clinical trial using allogeneic MSCs in human patients with acute MI showed no adverse immune-mediated reactions (Hare et al 2009).

Successful and safe allogeneic cell transfer would therefore be of enormous benefit, allowing banks of MSCs or CSCs to be stored for “off the shelf” use in the clinic. Allogeneic cell transfer is likely to be particularly pertinent in veterinary cardiology where the restricted gene pool in different dog breeds would make generation of breed specific cell banks particularly attractive.

The main aims we propose are to:

• Test the immune status of MSCs derived from Dobermans and other breeds.
• Explore regenerative mechanisms that require direct cell contact between MSCs and CSCs in in-vitro culture systems.
• Investigate small molecules that may potentiate theses regenerative interaction.

If time permits, towards the end of the PhD programme we will carry out a proof of concept study to inject allogeneic MSCs and CSCs into Doberman pinchers with advanced DCM and closely follow outcome at our small animal hospital using state of the art echocardiographic techniques, 24 hour ECG analysis and histopathology and immunocytochemistry following post mortem. T

his is an exciting opportunity to explore potential therapies for a common and incurable cardiac condition.

This project will be conducted within the Department of Veterinary Clinical Science at the Hawkshead (Hertfordshire) campus of the ÌÇÐÄvlogÊÓƵ. The ÌÇÐÄvlogÊÓƵ is the largest Veterinary College in the UK and has an outstanding reputation for clinical and research activities.

The successful candidate will be provided with training in cellular and molecular biology, isolation and identification of stem cells, and relevant immunological techniques.

Upon completion of the project the candidate will be well placed to progress into an academic or industrial career.

Applicants should hold, or expect to obtain, a minimum upper-second class honours degree (or equivalent) in a biological science.

This 3-year project is open to UK/EU and non-EU nationals but no funding is provided. Applicants must therefore be able to evidence their ability to provide self-arranged funding.

*Annual tuition fees for this project are currently: UK/EU nationals: £ 3,900 Non-EU nationals: £ 20,880

For Further information please contact Dr Jay Dudhia jdudhia@rvc.ac.uk or Dr David Connolly dconnolly@rvc.ac.uk for further information.

Please contact the supervisors in the first instance the apply via . See also the How to apply box .