Safety of intravenous mesenchymal stem cell therapy: a meta-analysis of randomized controlled trials

Habiba, Umm E1,2,3,*; Greene, David Lawrence1,2,3,4; Ahmad, Khalil5; Shamim, Sabiha1,2,3; Khan, Nasar1,2,3,4; Umer, Amna1,2,3

1Pak-American Hospital Pvt. Ltd., Jahangir Multiplex, Islamabad, Pakistan

2R3 Medical Research LLC, Scottsdale, AZ, USA

3R3 Stem Cell LLC, Scottsdale, AZ, USA

4Bello Bio Labs and Therapeutics Pvt. Ltd., Jahangir Multiplex, Islamabad, Pakistan

5Department of Statistics, Quaid-i-Azam University Islamabad, Islamabad, Pakistan

*Correspondence to: Umm E Habiba, uhabiba@r3stemcell.com or umehabiba617@gmail.com.

Abstract

Previous preclinical research and human trials have demonstrated that intravenous cell administration is a safe and successful treatment method for improving the quality of life in patients with a variety of illnesses. The purpose of this study was to evaluate the safety profile of mesenchymal stem cells administered intravenously. We explored PubMed, ScienceDirect, Web of Science, ClinicalTrials.gov, and the Cochrane Library for published research from their creation through December 2024, following PRISMA 2020 guidelines. Two researchers independently assessed the study’s inclusion and exclusion criteria, data extraction, and risk of bias assessment. Our meta-analysis includes 36 studies on mesenchymal stem cell therapy by intravenous method. The safety profile of mesenchymal stem cell therapy was evaluated across various adverse event categories using meta-analyses of randomized controlled trials. Twenty-two randomized controlled trials assessed general disorders and administration site conditions, showing no statistically significant increase in adverse event risk in the mesenchymal stem cell group compared to controls (log odds ratio [OR]: 0.29, 95% confidence interval [CI]: –0.15 to 0.73, P = 0.201). Similarly, analyses of musculoskeletal/connective tissue disorders (four randomized controlled trials, log OR: –0.26, 95% CI: –1.81 to 1.29, P = 0.742) and renal/urinary disorders (five randomized controlled trials, log OR: 0.30, 95% CI: –0.59 to 1.19, P = 0.511) revealed non-significant results. Conversely, a statistically significant increase in nervous system disorders was observed (thirteen randomized controlled trials, log OR: 0.54, 95% CI: –0.05 to 1.13, P = 0.072). Infection-related adverse events, evaluated in twenty randomized controlled trials, showed a slight but significant elevated risk in the mesenchymal stem cell group (log OR: –0.32, 95% CI: –0.61 to -0.02, P = 0.036). Gastrointestinal disorders (five randomized controlled trials, log OR: 0.00, 95% CI: –0.33 to 0.33, P = 0.988), respiratory/thoracic disorders (eight randomized controlled trials, log OR: –0.12, 95% CI: –0.67 to 0.42, P = 0.652), and immune system disorders (three randomized controlled trials, log OR: –0.97, 95% CI: –2.42 to 0.49, P = 0.193) did not show significant risk increases. Injury and procedural complications (five randomized controlled trials) also demonstrated a non-significant trend. Heterogeneity was minimal across all analyses, and no substantial publication bias or influential studies were identified. While most findings support the safety of mesenchymal stem cell therapies, significant results for nervous system and infection-related adverse events warrant further investigation. We conclude that intravenous delivery of mesenchymal stem cells is safe for many conditions. However, large-scale randomized controlled trials are required to confirm the findings.

静脉间充质干细胞疗法的安全性：随机对照试验meta分析

摘要

以往的临床前研究和人体试验表明，静脉注射细胞是一种安全、成功的治疗方法，可改善各种疾病患者的生活质量。为评估间充质干细胞（MSCs）静脉给药的安全性，文章遵循PRISMA 2020指南，检索了PubMed、ScienceDirect、Web of Science、ClinicalTrials.gov和Cochrane图书馆从建库到2024年12月发表的研究。两名研究人员独立评估了研究的纳入和排除标准、数据提取和偏倚风险评估。此meta分析包括 36 项关于间充质干细胞静脉注射疗法的研究。通过对随机对照试验（RCTs）进行荟萃分析，评估了间充质干细胞（MSC）疗法在各类不良事件（AE）中的安全性。22项随机对照试验评估了一般疾病和用药部位情况，结果显示间充质干细胞组的不良事件风险与对照组相比无统计学意义上的显著增加（log odds ratio：0.29，95% CI：-0.15至0.73，P = 0.201）。同样，对肌肉骨骼/结缔组织疾病（4 项 RCT，对数奇数比 [OR]：-0.26，95% CI：-1.81 至 1.29，P= 0.742）和肾脏/泌尿系统疾病（5 项 RCT，对数 OR：0.30，95% CI：-0.59 至 1.19，P= 0.511）的分析显示结果不显著。相反，神经系统疾病的发病率却有统计学意义的增加（13 项研究，对数 OR：0.54，95% CI：-0.05 至 1.13，P= 0.072）。在 20 项研究中对感染相关的 AE 进行了评估，结果显示间充质干细胞组的风险略有上升，但上升幅度较大（对数 OR：-0.32，95% CI：-0.61 至 -0.02，P= 0.036）。胃肠道疾病（5 项研究，对数 OR：0.00，95% CI：-0.33 至 0.33，P= 0.988）、呼吸系统/胸部疾病（8 项研究，对数 OR：-0.12，95% CI：-0.67 至 0.42，P= 0.652）和免疫系统疾病（3 项研究，对数 OR：-0.97，95% CI：-2.42 至 0.49，P= 0.193）未显示风险显著增加。损伤和手术并发症（5项研究）也显示出非显著趋势。在所有分析中，异质性极小，没有发现严重的发表偏倚或有影响的研究。虽然大多数研究结果支持间充质干细胞疗法的安全性，但神经系统和感染相关的AEs的显著结果值得进一步研究。以上结果表明，静脉注射间充质干细胞疗法对许多疾病都是安全的。然而，需要进行大规模的临床试验来进一步证实这些结果。