Allopurinol/uricase and ibuprofen enhance engraftment of cardiomyocyte-enriched human embryonic stem cells and improve cardiac function following myocardial injury.
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 10(6) (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 alpha-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.
Kofidis
Theo
T
Cardiothoracic Surgery/Falk Research Center, Stanford University Medical School, Stanford, CA, USA. kofidis@thg.mh.hannover.de
Lebl
Darren R
DR
Swijnenburg
Rutger-Jan
RJ
Greeve
Joan M
JM
Klima
Uwe
U
Gold
Joseph
J
Xu
Chunhui
C
Robbins
Robert C
RC
D000208:Acute Disease; D000493:Allopurinol / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002478:Cells, Cultured; D003131:Combined Modality Therapy / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal / Q000379:methods; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000637:transplantation; D033581:Stem Cell Transplantation / Q000379:methods*; D013318:Stroke Volume / Q000502:physiology; D014503:Urate Oxidase / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000493:Allopurinol; D014503:Urate Oxidase; D007052:Ibuprofen