不同细胞疗法治疗严重肢体缺血的系统评价和网状Meta分析

Systematic evaluation and network meta-analysis of different cell therapies in the treatment of critical limb ischemia

目的 系统评价纯化的CD34^(+)细胞(PCCs)、骨髓单核细胞(BMMNCs)、骨髓间充质干细胞(BMMSCs)和外周血单核细胞(PBMNCs)4种常见的细胞疗法在治疗严重肢体缺血(CLI)时的有效性和安全性。方法 计算机检索PubMed、Scopus、Embase、Cochrane对照试验注册中心、Web of Science数据库,检索时限为各数据库建库起至2023年6月,收集PCCs、BMMNCs、BMMSCs和PBMNCs 4种不同细胞疗法对比其他细胞疗法或标准疗法(ST)治疗CLI的疗效和安全性的随机对照试验(RCT),结局指标包括截肢率、踝肱指数(ABI)、经皮氧分压(TCPO_(2))、溃疡愈合率、无痛步行距离(PFWD)和血管生成情况。提取符合纳入标准的临床研究资料,采用RoB 2.0工具进行偏倚风险评估,使用Stata 15.0软件进行统计分析。结果 Meta分析共纳入22项研究,涉及1 318名患者,治疗组涉及4种细胞疗法,分别是PCCs、BMMNCs、BMMSCs、PBMNCs。网状Meta分析显示,4种细胞疗法组截肢率均低于ST组,仅PBMNCs组差异具有统计学意义(P<0.05);4种细胞干预措施在提高ABI方面均优于ST组(P<0.05),且BMMNCs对ABI的提高效果最显著;PBMNCs、BMMNCs组提高TCPO_(2)方面与ST、BMMSCs相比差异有统计学意义(P<0.05);4种细胞干预措施在提高溃疡愈合率方面均优于ST,但BMMNCs组与ST组比较差异无统计学意义(P>0.05),其余3组溃疡愈合率均显著高于ST组(P<0.05),且PBMNCs组、BMMSCs组的溃疡愈合率显著高于BMMNCs组(P<0.05);BMMSCs移植后对患者PFWD的提高显著优于ST(P<0.05),PBMNCs、BMMNCs组与ST组比较差异无统计学意义(P>0.05);BMMSCs、BMMNCs、PBMNCs这3种细胞疗法改善血管生成的效果均优于ST,且BMMSCs疗效显著优于BMMNCs和PBMNCs,差异均有统计学意义(P<0.05)。结论 4种细胞疗法都可以在不同程度上改善CLI患者的预后。PBMNCs移植后截肢率最低,且改善TCPO_(2)和提高溃疡愈合率的效果最显著;BMMNCs改善ABI的效果最显著;在PFWD和血管生成方面,BMMSCs表现出明显的优势。

OBJECTIVE To systematically evaluate the efficacy and safety of the four most common cell therapies,namely purified CD34^(+)(PCCs),bone marrow mononuclear cells(BMMNCs),bone marrow mesenchymal stem cells(BMMSCs)and peripheral blood mononuclear cells(PBMNCs)in the treatment of critical limb ischemia(CLI).METHODS PubMed,Scopus,Embase,Cochrane Central Register of Controlled Trials(CENTRAL)and Web of Science databases were searched from the establishment of each database to June 2023 to collect randomized controlled trials(RCTs)comparing the efficacy and safety of four different cell therapies,namely PCCs,BMMNCs,BMMSCs and PBMNCs,with other cell therapies or standard therapy(ST)in the treatment of CLI.The outcomes indexes included amputation rate,ankle-brachial index(ABI),transcutaneous oxygen partial pressure(TCPO_(2)),ulcer healing rate,pain-free walking distance(PFWD)and angiogenesis.After data extraction from clinical studies that met the inclusion criteria,the RoB 2.0 tool was used to assess the risk of bias,and Stata 15.0 software was used for statistical analysis.RESULTS Meta-analysis included 22 studies,involving 1318 patients.The treatment groups involved 4 types of cell therapies,namely PCCs,BMMNCs,BMMSCs,and PBMNCs.Network meta-analysis showed that the amputation rates of the four cell therapies groups were lower than that of ST group,and only the difference in PBMNCs group was statistically significant(P<0.05).Four cell interventions were better than ST in improving ABI(P<0.05),and BMMNCs had the most significant effect on improving ABI.PBMNCs and BMMNCs groups had statistically significant differences in improving TCPO_(2),compared with ST group and BMMSCs group(P<0.05).Four cell interventions were better than ST in improving ulcer healing rate,among which BMMNCs group had no statistical difference with ST group(P>0.05);ulcer healing rates of the other three groups were higher than that of ST group(P<0.05),and those of PBMNCs and BMMSCs groups were significantly higher than that of BMMNCs group(P<0.05).BMMSCs group had a significantly better effect on improving the PFWD of patients than the ST group after transplantation,with statistical significance(P<0.05),but there was no significant difference in PBMNCs and BMMNCs groups compared with ST group(P>0.05).The three cell therapies of BMMSCs,BMMNCs and PBMNCs had a significantly better effect on angiogenesis than the ST group,and the BMMSCs group had a significantly better effect than the BMMNCs and PBMNCs groups,with statistical significance(P<0.05).CONCLUSIONS The four cell therapies can improve the prognosis of CLI patients to varying degrees.PBMNCs show the lowest amputation rate after transplantation and have the most significant effect on improving TCPO_(2) and improving the ulcer healing rate.BMMNCs possess the most significant effect on improving ABI.BMMSCs represent obvious advantages in PFWD and angiogenesis.