Small molecules and activation of heart recovery after injury
Research type
Research Study
Full title
Identification of small molecules for induction of adult epicardial activation after injury
IRAS ID
228567
Contact name
Paul Riley
Contact email
Sponsor organisation
University of Oxford
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Research Summary
Heart attack, results in the instantaneous death of millions of cardiac muscle cells, and the creation of a thick non-contractile fibrotic scar which ultimately leads to heart failure. Currently, the only treatment is heart transplantation. Despite a decade of research on cardiac stem cells the clinical study results have generally been disappointing, due to sub-optimal cell retention/ integration in the heart after transplantation.
This study aims to exploit the potential of resident cells within the heart to repair and restore lost tissue.
Research from Professor Riley’s group has demonstrated that the outer cell layer of the heart, the epicardium, can be activated during heart attack. Riley recently determined that adult epicardial-derived cells (EPDCs) when stimulated by a small protein (thymosin β4) can give rise to new cardiovascular cell types, including cardiac muscle cells. Whilst thymosin β4 provided critical proof on the regenerative potential of the adult EPDCs, the efficiency of cardiac cell derivation was low. This highlights the urgent need for screening for more efficacious small molecules that would lead to efficient epicardial activation, and replacement of the lost cardiac muscle cells following heart attack.
The Riley group researchers (Dept. of Physiology, Anatomy & Genetics) will receive cardiac biopsies, isolated from patients undergoing valve replacement surgery by Prof. Taggart (Nuffield Department of Surgical Sciences, John Radcliffe Hospital), in order to isolate EPDCs. This study will compare the characteristics of EPDCs derived from both the atrial and ventricular compartments of the adult heart, and will use primary cultures in chemical screens with the goal to identify small molecules that stimulate the activation of resident adult EPDCs, to give rise to new cardiovascular cells following heart attack. It is hoped that the outcome of this study will facilitate the development of regenerative therapies to treat patients with ischaemic heart disease.Summary of Results
The project aim was to obtain right atrial appendage biopsies from patients at the John Radcliffe Hospital undergoing right coronary artery bypass surgery (CABG) or cardiac valve repair/replacement. The intention was to derive epicardial cell cultures (cells lining the outside of the heart) from the biopsies according to a previously published protocol within the group: https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbT-2Fr-2FMtNcEJagWfoqU8vKsKkQhGH32E0mNljGQqzGMILd2fY0KiO2OrkT09dBps-2FydGL-2F6Zqx1EkZ9aNwY7LG2gpUnL-2BzLj-2FKYYz06GOyAwfebgE_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YLwgPDviWl-2F43stsYNv1HAeKW8PLDpKAucpMw8jNUvGUNKDQRs-2BXeQ7NQkFDfcZ0r7KHgirB4a5QbM5R3xuWEFaDlDVx5jAPxbk5dADy-2BybWmV8tpsYjY8fpAM97pPtiWhjEXuOlfaOIKCWpWhcEDJnSBTHMrewxG-2BnQEkTqEQ2Fw-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C617541c20c1946a9ff9008db2b827626%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638151611546213977%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=Anh%2FdwITVLqhs%2FHauewaXIvanRBbjpouhn%2FmBI76adg%3D&reserved=0
The intention was to utilise these primary cultures in chemical screens for small molecule drugs that might activate the epicardial cells to undergo a cell shape change, induce migration and give rise to important cell type derivatives (for example, endothelial cells, vascular smooth muscle cells) that are predicted to be important for re-vascularising the injured adult heart after a heart attack. Unfortunately, due to a combination of staffing issues affecting the patient recruitment; failure to notify us of available samples and the biopsies being too small to sustain viable cell cultures we had to revert to an alternative source of tissue from collaborators in Gottingen, Germany and ultimately adopted an alternative model of directed differentiation of human induced pluripotent stem cells into epicardial cells to facilitate the drug screening programme.We received 7 samples from the JR site as part of this protocol (out of the 20 anticipated) none of which facilitated the planned primary cell cultures as part of the OxStem Cardio programme of small molecule drug discovery.
REC name
London - City & East Research Ethics Committee
REC reference
18/LO/0118
Date of REC Opinion
26 Jan 2018
REC opinion
Further Information Favourable Opinion