Therapeutic angiogenesis by transplantation of bone marrow stem cells

在日本进行的多中心研究（TACT-1研究组）中，在103例缺血肢体患者中建立了自体骨髓单个核细胞（BM-MNC）移植治疗性血管生成。2年随访研究（22例患者）证实了安全性和有效性。CD 34 ^+细胞表达bFGF>>VEGF>Angiopoietin-1，而CD 34 ^+细胞主要表达其受体。在BM-MNC植入肢体中，踝臂压力指数（ABI）从基线时的0.57增加到第4周的0.66和第24周的0.64（P<0.0001）。84例患者中有70例患者的缺血肢体静息痛消退，其疼痛限制性平板步行时间显著改善（从基线时的1.4 min增加到第4周的3.6 min和第24周的4.2 min，P<0.0001）。73条患肢中54条患肢缺血性溃疡或坏疽愈合，包括保肢成功。免疫组化分析显示，新的毛细血管形成与Ki-67阳性增殖内皮细胞显着增加。基于TACT-1研究和使用猪模型的临床前实验的结果，我们在三名患有缺血性冬眠心肌的无选择患者（n=3）中使用基于导管的BM-MNC植入进行单一细胞治疗的临床试验。0.2用27 G针头通过导管将1 ml BM-MNC注射到20个不同部位（总计1x10^8个细胞）。局部灌注（SPECT，NOGA心室造影）观察到缺血区心绞痛发生率显著降低，室壁运动改善。在1.5年内每月进行一次的24小时霍尔特记录中没有明显的心律失常。因此，基于细胞的缺血性心脏病的研究性治疗被证明是安全可行的。

Therapeutic angiogenesis by transplantation of autologous bone marrow mononuclear cells(BM-MNC) was established in 103 patients with ischemic limbs by multi-center study(TACT-1 Study Group) in Japan. Safety and efficacy was approved with 2-year follow-up study(22 patients). CD34^+ cells expressed bFGF>>VEGF>angiopoietin-1, while CD34^+ cells predominantly expressed their receptors. In BM-MNC-implanted limbs, ankle-brachial pressure index(ABI) was increased from 0.57 at baseline to 0.66 at week 4 and 0.64 at week 24 (P<0.0001). Rest pain in ischemic limbs was regressed in 70 of 84 patients, and their pain-limited treadmill walking time was significantly improved(from 1.4 min at baseline to 3.6 at week 4 and 4.2 at week 24,P<0.0001). Ischemic ulcers or gangrenes were healed in 54 of 73 limbs including successful limb salvage. Immunohistochemical analysis revealed a striking increase in new capillary formation with Ki-67 positive proliferating endothelial cells. On basis of the results of TACT-1 Study and pre-clinical experiments using porcine models, we performed the clinical trial of a sole cell therapy using catheter-based BM-MNC implantation in three no-option patients(n=3) with ischemic hibernating myocardium. 0.2 ml of BM-MNC was injected into 20 different sites(total 1x10^8 cells) via catheter with a 27G needle. Angina occurrence decreased dramatically and improvement in wall motion was observed in ischemic area with regional perfusion(SPECT, NOGA ventriography). There was no substantial arrhythmia on 24 h Holter recordings performed monthly for 1.5 year. Thus, cell-based investigational therapies for ischemic heart diseases were shown to be safe and feasible.