Kofidis Theo, Lebl Darren R, Swijnenburg Rutger-Jan, Greeve Joan M, Klima Uwe, Robbins Robert C
Cardiothoracic Surgery/Falk Research Center, Stanford University Medical School, Stanford, CA, USA.
Eur J Cardiothorac Surg. 2006 Jan;29(1):50-5. doi: 10.1016/j.ejcts.2005.10.015. Epub 2005 Dec 6.
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.
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.
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.
Allopurinol/uricase and ibuprofen enhance differentiated hESC-engraftment and myocardial restoration following transplantation into the injured heart.
干细胞移植的一个主要限制是早期供体细胞死亡。在此，我们试图通过移植富含心肌细胞的人胚胎干细胞（hESC）以及用细胞保护剂（别嘌醇+尿酸酶）和抗炎剂（布洛芬）对受体进行治疗，来促进损伤后的心肌修复。
在严重联合免疫缺陷（SCID）-米色小鼠的左前降支（LAD）结扎后，我们将10⁶个（15% hESC衍生的心肌细胞）绿色荧光蛋白（GFP+）hESC注射到梗死区域。在第一组中，在细胞移植前3天腹腔注射1.6毫克别嘌醇和0.2毫克尿酸酶。在第二组中，在细胞植入前后，将0.35毫克/毫升的布洛芬添加到饮用水中。在第三组中，结扎LAD并给予别嘌醇/尿酸酶但不进行细胞治疗。在第四组中，将布洛芬添加到饮用水中，结扎LAD且不进行额外的细胞治疗。在第五组中，仅进行细胞移植。第六组为梗死对照组，第七组为假手术小鼠（所有组：n = 5）。3周后，我们通过磁共振成像（4.7 T）评估心脏功能（射血分数（EF））。收获心脏进行组织学检查。
分化的hESC形成簇并表达α-肌动蛋白和连接蛋白43。细胞治疗改善了心脏功能，与梗死对照组相比，在布洛芬和别嘌醇治疗组（+细胞移植）中效果最佳[EF：第一组：76.6±8.6%，第二组：78.6±7.3%，第三组：58.1±5.7%，第四组：53.9±5.2%，第五组：57.7±7.5%，第六组：43.5±4.3%，第七组：66.3±7.8%]。我们在任何组中均未观察到肿瘤。
别嘌醇/尿酸酶和布洛芬可增强分化的hESC移植到受损心脏后的植入及心肌修复。
