Embryonic stem cell-derived cardiomyocytes as a model system for cardiac investigations

Project background

The incidence of heart failure is increasing due to an ageing population and success in treating heart attacks. Patients with damage to the myocardium after a heart attack are at high risk for progressive heart failure. Animal models can be used to investigate heart attacks and progressive heart failure, and have contributed to the advances in both drug treatments and devices. Currently, primary isolated cardiac myocytes can be isolated from animal hearts, however these have a number of limitations predominantly due to the limited plasticity of the heart. Isolated cardiac myocytes do not divide and undergo rapid de-differentiation limiting the useful culture period to one to two days.

Why we funded it

This Project Grant aims to assess the potential of embryonic stem cell (ESC)-derived cardiac cells to replace the need for primary isolated cardiac myocytes from rats, rabbits or guinea pigs.    

The isolation of cardiac myocytes requires removal of the heart, which is then enzymatically digested to isolate the cells. The animal is not subject to any procedures prior to cell isolation. Replacing the primary cardiac myocytes with cells derived from ESCs has the potential to replace up to 180 animals annually in Professor Harding’s group. Approximately 1,200 papers were published in 2005 using the isolated cardiac myocyte preparation requiring between 10 and 50 animals per publication, providing further scope for replacement internationally.

Research methods

Embryoid bodies formed from aggregated ESCs, derived from mice or humans, will be used to generated ESC-derived myocytes (ESCMs). Embryoid bodies are initiated in hanging drops and sustained in differentiation media before single cardiomyocytes can be isolated. The spontaneous appearance of beating cardiac myocytes occurs in cells derived from both species, and can beat for up to 70 days in culture as the cells mature. The newly derived ESCMs will be characterised to assess the basic physiological characteristics of the cell including morphology, electrophysiology and intracellular signalling. These characteristics will then be compared to primary adult cardiac myocytes. After characterisation, the contractile response of the ESCMs to selected neurohormonal agents currently being investigated for their roles in heart failure will be analysed.  

Földes G et al. (2014). Immunosuppressive agents modulate function, growth, and survival of cardiomyocytes and endothelial cells derived from human embryonic stem cells. Stem Cells Dev. 23(5):467-76. doi: 10.1089/scd.2013.0229

Mioulane M et al. (2012). Development of high content imaging methods for cell death detection in human pluripotent stem cell-derived cardiomyocytes. Journal of cardiovascular translational research 5:593-604. doi: 10.1007/s12265-012-9396-1

Földes G et al. (2011). Modulation of human embryonic stem cell-derived cardiomyocyte growth: a testbed for studying human cardiac hypertrophy? Journal of molecular and cellular cardiology 50:367-76. doi:10.1016/j.yjmcc.2010.10.029

Földes G et al. (2010). Innate immunity in human embryonic stem cells: comparison with adult human endothelial cells. PLoS ONE 5(5):e10501. doi: 10.1371/journal.pone.0010501

Abdul Kadir SH et al. (2009). Embryonic stem cell-derived cardiomyocytes as a model to study fetal arrhythmia related to maternal disease. Journal of Cellular and Molecular Medicine 13(9b):3730-3741. doi: 10.1111/j.1582-4934.2009.00741.x

Brito-Martins M et al. (2008). Beta (1)- and beta (2) adrenoreceptor responses in cardiomyocytes derived from human embryonic stem cells: comparison with failing and non-failing adult human heart. British Journal of Pharmacology 153:751-759. doi: 10.1038/sj.bjp.0707619

Jawad H et al. (2008). Myocardial tissue engineering. British medical bulletin 87(1):31-47. doi: 10.1093/bmb/ldn026

Harding SE et al. (2007). The human embryonic stem cell-derived cardiomyocyte as a pharmacological model. Pharmacology & Therapeutics 113:341-353. doi: 10.1016/j.pharmthera.2006.08.008

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Project grant

Status

Closed

Principal investigator

Professor Sian Harding

Institution

Imperial College London

Co-Investigator

Dr Nadire Ali

Grant reference number

G0600373/1

Award date

Oct 2006 - Oct 2009

Grant amount

£200,868