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Eur J Cardiothorac Surg 2006;29:50-55
© 2006 Elsevier Science NL

Allopurinol/uricase and ibuprofen enhance engraftment of cardiomyocyte-enriched human embryonic stem cells and improve cardiac function following myocardial injury

^a Cardiothoracic Surgery/Falk Research Center, Stanford University Medical School, Stanford, CA, USA
^b Department of Radiology, Stanford University Medical School, Stanford, CA, USA
^c Geron Corporation, Menlo Park, CA, USA
^d Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl Neuberg Street 1, 30625 Hannover, Germany

Received 27 June 2005; received in revised form 21 September 2005; accepted 7 October 2005.

^_* Corresponding author. Present address: Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl Neuberg Street 1, 30625 Hannover, Germany. Tel.: +49 511 532 6580; fax: +49 511 532 5404. (Email: kofidis{at}thg.mh-hannover.de).

Objective: A major limitation of stem cell transfer is early donor-cell death. Here, we seek to enhance myocardial repair following injury through transplantation of cardiomyocyte-enriched human embryonic stem cells (hESC) and recipient treatment with cytoprotective (allopurinol + uricase) and anti-inflammatory (ibuprofen) agents. Methods: We injected 10⁶ (15% hESC-derived cardiomyocytes) green fluorescent protein (GFP+) hESC in the infarcted area following left anterior descending artery (LAD)-ligation in SCID-beige mice. In Group I, 1.6 mg allopurinol and 0.2 mg of uricase were injected i.p. for 3 days prior to cell transplantation. In Group II, 0.35 mg/ml of ibuprofen were added to the drinking water before and after cell implantation. In Group III, the LAD was ligated and allopurinol/uricase was administered without cell treatment. In Group IV, ibuprofen was added to the drinking water and the LAD was ligated without additional cell treatment. In Group V, only cells were transplanted. Group VI involved infarcted controls and Group VII involved sham-operated mice (all groups: n = 5). We evaluated heart function (ejection fraction (EF)) by MRI (4.7 T) 3 weeks later. The hearts were harvested for histology. Results: Differentiated hESC formed clusters and expressed -sarcomeric actin and Connexin 43. Cell treatment improved heart function, which was best in the ibuprofen- and allopurinol-treated groups (+cell transfer), compared to the infarcted controls [EF: Group I: 76.6 ± 8.6%, Group II: 78.6 ± 7.3%, Group III: 58.1 ± 5.7%, Group IV: 53.9 ± 5.2%, Group V: 57.7 ± 7.5%, Group VI: 43.5 ± 4.3%, and Group VII: 66.3 ± 7.8%]. We did not observe tumors in any group. Conclusions: Allopurinol/uricase and ibuprofen enhance differentiated hESC-engraftment and myocardial restoration following transplantation into the injured heart.

Key Words: Embryonic stem cells • Myocardial restoration • Ischemic heart disease

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