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15 Efficient cardiac differentiation of human induced pluripotent stem cells, that engraft and protect against ischaemic damage in the infarcted rat heart
  1. C A Carr1,
  2. L Carpenter2,
  3. C T Yang3,
  4. D J Stuckey1,
  5. K Clarke1,
  6. S M Watt2
  1. 1Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, UK
  2. 2Stem Cell Research Laboratory, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK
  3. 3Department of Cardiovascular Medicine, University of Oxford, Oxford, UK

Abstract

Induced pluripotent stem (iPS) cells provide a promising source of cardiac progenitor cells for administration to the infarcted heart. Here, we describe a protocol for efficient, serum free, directed differentiation of human iPS cells, as a monolayer, that yields a mixed population in which cardiomyocytes, endothelium and smooth muscle cells constitute over 50% of the differentiated population, with no additional selection strategies utilised. GFP positive cardiac progenitors from human iPS cells (2×106) were administered by direct injection into the myocardium of athymic nude rats following 50 min of ischaemia. Cardiac function was measured using MRI at 2 days, 2, 6 and 10 weeks. At 10 weeks the hearts were removed for histology. By 6 weeks, control infarcted hearts (n=5) had significantly larger end systolic volumes and lower ejection fractions than sham operated hearts (n=3) whereas hearts treated with iPS-derived cardiac differentiated cells (n=4) maintained cardiac function; such that by 10 weeks the end systolic volumes and ejection fractions were not significantly different from those of the sham operated animals (ejection fraction at 10 weeks: sham 77±5%, infarct 45±9% (p<0.05 vs sham), iPS 62±4%). Histological analysis showed that the human iPS-derived cardiac progenitor cells engrafted, differentiated into cardiomyocytes and smooth muscle, and persisted for at least 10 weeks post-infarct. Thus efficient directed differentiation of human iPS cells towards the cardiac lineage generates cells that can prevent loss of heart function after ischaemic heart damage.

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