Therapeutic angiogenesis by transplantation of bone marrow stem cells

通过多中心研究（act -1研究组），在103例肢体缺血患者中建立了自体骨髓单个核细胞（BM-MNC）的治疗性血管生成。安全性和有效性通过2年随访研究（22例）获得批准。CD34^+细胞表达bFGF>>VEGF>血管生成素-1，而CD34^+细胞主要表达其受体。在bm - mnc植入的肢体中，踝关节-肱压力指数（ABI）从基线的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例缺血肢体的静息疼痛得到缓解，疼痛受限的跑步机行走时间显著改善（从基线时的1.4分钟到第4周时的3.6分钟和第24周时的4.2分钟，P<0.0001）。73条肢体中54条的缺血性溃疡或坏疽愈合，包括成功的肢体保留。免疫组织化学分析显示Ki-67阳性增殖内皮细胞新毛细血管形成显著增加。基于act -1研究的结果和猪模型的临床前实验，我们对3例无选择的缺血性冬眠心肌患者（n=3）进行了单细胞移植术的临床试验。取BM-MNC 0.2 ml，用27G针经导管注入20个不同部位（共1 × 10^8个细胞）。心绞痛发生率显著降低，局部灌注缺血区壁运动改善（SPECT、NOGA心室造影）。每月24小时动态心电图记录1年半无明显心律失常。因此，基于细胞的研究性治疗缺血性心脏病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.