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中华细胞与干细胞杂志(电子版) ›› 2023, Vol. 13 ›› Issue (04) : 247 -256. doi: 10.3877/cma.j.issn.2095-1221.2023.04.008

综述

间充质干细胞治疗新冠病毒感染的临床研究进展
王红敏, 谢云波, 王彦虎, 王福生()   
  1. 100039 北京,中国人民解放军总医院第五医学中心感染病医学部,国家感染性疾病临床医学研究中心;230001 合肥,中国科学技术大学附属第一医院,中国科学技术大学生命科学与医学部
    100039 北京,中国人民解放军总医院第五医学中心感染病医学部,国家感染性疾病临床医学研究中心;100039 北京,解放军医学院研究生院
    100039 北京,中国人民解放军总医院第五医学中心感染病医学部,国家感染性疾病临床医学研究中心;230001 合肥,中国科学技术大学附属第一医院,中国科学技术大学生命科学与医学部;100039 北京,解放军医学院研究生院
  • 收稿日期:2023-06-15 出版日期:2023-08-01
  • 通信作者: 王福生
  • 基金资助:
    国家感染性疾病临床医学研究中心专项(413FZT1)

The advance of clinical research in mesenchymal stem cell treatment for COVID-19

Hongmin Wang, Yunbo Xie, Yanhu Wang, Fusheng Wang()   

  1. Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; The First Afiliated Hospital of USTC, Division of L ife Sciences and Medicine, University of Science and Technology ofChina, Hefei 230001, China
    Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; Chinese PLA General Hospital, Beijing 100853, China
    Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; The First Afiliated Hospital of USTC, Division of L ife Sciences and Medicine, University of Science and Technology ofChina, Hefei 230001, China; Chinese PLA General Hospital, Beijing 100853, China
  • Received:2023-06-15 Published:2023-08-01
  • Corresponding author: Fusheng Wang
引用本文:

王红敏, 谢云波, 王彦虎, 王福生. 间充质干细胞治疗新冠病毒感染的临床研究进展[J]. 中华细胞与干细胞杂志(电子版), 2023, 13(04): 247-256.

Hongmin Wang, Yunbo Xie, Yanhu Wang, Fusheng Wang. The advance of clinical research in mesenchymal stem cell treatment for COVID-19[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 247-256.

自2019年底新冠病毒感染疫情暴发以来,间充质干细胞(MSCs)因其具有减轻肺脏炎症,促进肺组织修复和免疫调节作用,MSCs治疗已成为一种新的免疫疗法。目前,已有多项MSCs治疗新型冠状病毒肺炎(COVID-19)的临床试验取得进展,结果表明COVID-19患者的肺部病变、临床症状及免疫相关指标等均改善,且未观察到治疗相关的严重不良反应,证明了MSCs治疗的安全性和有效性。但是,MSCs治疗COVID-19的临床应用仍存在一些问题和挑战,如尚无标准的MSCs治疗方案、未明确MSCs治疗的最佳适应人群、缺乏对MSCs治疗COVID-19远期疗效的随访等,这些需要进一步开展大范围深入的临床研究去解决。本文对近三年来目前国内外已注册和发表的MSCs治疗COVID-19的临床研究进行了综述。

Since the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) epidemic in December 2019, mesenchymal stem cells (MSCs) have become an important immunotherapy because of their immune regulation of lung inflammation and promoting lung tissue repair. To date, many clinical researches have shown that MSCs therapy may alleviate pulmonary lesions, clinical symptoms and immunological indices and no treatment-related adverse events were observed, which have proved the safety and efficacy of MSCs treatment for coronavirus disease 2019 (COVID-19) . However, there are still some challenges for the clinical application of MSCs treatment for COVID-19, for example, lack of standard treatment regimen, unidentified susceptible patients and absence of long-term efficiency. Clinical trials with larger sample sizes are necessary. This review summarizes the clinical researches on MSCs treatment for COVID-19 registered and published worldwide in recent years.

图1 ClinicalTrial注册MSCs治疗COVID-19项目全球分布情况注:来源https://clinicaltrials.gov/截止2023年6月30日
图2 ClinicalTrial注册MSCs治疗COVID-19临床试验分期及进度注:来源https://clinicaltrials.gov/截止2023年6月30日
表1 中国临床试验注册中心注册MSCs治疗COVID-19项目
注册号 注册时间 研究机构 注册题目
ChiCTR2000031494 2020/4/2 黄石市中医医院 间充质干细胞治疗重症新型冠状病毒肺炎(COVID-19)的临床研究
ChiCTR2000031430 2020/3/31 中国人民解放军总医院第五医学中心 人间充质干细胞治疗新型冠状病毒肺炎(COVID-19)患者肺间质性损害的临床研究
ChiCTR2000031319 2020/3/27 武汉大学人民医院 异体人牙髓间充质干细胞治疗新型冠状病毒肺炎(COVID-19)重症肺炎的安全性和有效性研究
ChiCTR2000031139 2020/3/22 武汉市金银潭医院(武汉市传染病医院) 人胚干细胞来源M细胞(CAStem)治疗新型冠状病毒肺炎(COVID-19)相关肺纤维化的安全性和有效性研究
ChiCTR2000030944 2020/3/18 南昌大学第二附属医院 人自然杀伤细胞联合间充质干细胞治疗重症新型冠状病毒肺炎(COVID-19)的临床研究
ChiCTR2000030866 2020/3/16 长沙市第一医院 脐带间充质干细胞治疗重型和危重型新型冠状病毒肺炎(COVID-19)的开放性临床观察研究
ChiCTR2000030835 2020/3/15 新乡医学院第一附属医院 间充质干细胞(MSC)治疗重型新型冠状病毒肺炎(COVID-19)的有效性临床研究
ChiCTR2000030261 2020/2/26 无锡市第五人民医院 间充质干细胞外泌体雾化吸入治疗新型冠状病毒肺炎(COVID-19)的关键技术研究
ChiCTR2000030173 2020/2/24 湖南源品细胞生物科技有限公司 脐带间充质干细胞治疗新型冠状病毒肺炎(COVID-19)关键技术攻关与临床应用示范
ChiCTR2000030138 2020/2/24 中国人民解放军总医院 人间充质干细胞治疗重症新型冠状病毒(COVID-19)感染肺炎临床研究
ChiCTR2000030116 2020/2/23 南昌大学第一附属医院 人脐带间充质干细胞治疗重症新型冠状病毒肺炎(COVID-19)致急性呼吸窘迫综合征的安全性和有效性研究
ChiCTR2000030088 2020/2/22 解放军总医院第六医学中心 脐带华通胶源间充质干细胞治疗重症新型冠状病毒肺炎(COVID-19)
ChiCTR2000030020 2020/2/20 南华大学附属第二医院 间充质干细胞治疗新型冠状病毒肺炎(COVID-19)的临床应用及其相关基础研究
ChiCTR2000029990 2020/2/18 中国医学科学院基础医学研究所 人间充质工细胞治疗新型冠状病毒感染肺炎(COVID-19)的临床研究
ChiCTR2000029606 2020/2/7 浙江大学医学院附属第一医院 官血干细胞治疗新型冠状病毒肺炎(COVID-19)急性肺损伤(肺炎)的临床研究
ChiCTR2000029580 2020/2/5 华中科技大学同济医学院附属同济医院 芦可替尼联合输注间充质干细胞治疗重症新型冠状病毒肺炎(COVID-19)患者的前瞻性、单盲、随机对照临床研究
ChiCTR2300069181 2023/3/8 华中科技大学协和深圳医院 脐带间充质干细胞外泌体治疗新冠病毒感染后慢性咳嗽的安全性及有效性临床研究
注册号 团队PI 分期 例数 起止时间
ChiCTR2000031494 冯旰珠 I期 试验组18例;对照组18例 2020.2.1- 2020.12.2
ChiCTR2000031430 王福生 II期 试验组100例;对照组100例 2020.3.14-2021.12.31
ChiCTR2000031319 叶青松,周晨亮 / 试验组10例;对照组10例 2020.4.1- 2020.7.31
ChiCTR2000031139 张定宇 / 试验组20例 2020.3.20-2121.3.19
ChiCTR2000030944 叶小群 I期 试验组10例;对照组10例 2020.3.1-2020.8.31
ChiCTR2000030866 谢元林 / 实验组30例;无对照 2020.2.1-2020.12.31
ChiCTR2000030835 窦启锋 / 高剂量组10例;低剂量组10例 2020.2.14-2021.2.14
ChiCTR2000030261 储美萍 / 实验组13例;对照组13例 2020.2.28-2020.5.31
ChiCTR2000030173 薛志刚 / 实验组30例;对照组30例 2020.2.17-2020.4.17
ChiCTR2000030138 薄剑,吕传柱 II期 实验组30例;对照组30例 2020.2.24-2020.5.31
ChiCTR2000030116 张伟 / 高剂量组30例;低剂量组30例 2020.2.1- 2020.8.31
ChiCTR2000030088 高连如 / 实验组20例;对照组20例 2020.3.1-2021.12.31
ChiCTR2000030020 罗志刚 / 实验组20例 2020.2.6-2.22.2.5
ChiCTR2000029990 赵春华/金荣华 I期+II期 实验组60例;对照组60例 2020.1.30-2020.3.31
ChiCTR2000029606 李兰娟/徐小微/项春生 / 实验组A:18例;对照组A:15例;试验组B1:10例;试验组B2:10例;对照组B :10例 2020.1.5-2022.12.31
ChiCTR2000029580 周剑峰 / 试验组35例;对照组35例 2020.1.31- 2020.12.31
ChiCTR2300069181 杜冀晖 / 试验组40例;对照组20例 2023.2.15-2024.2.15
图3 MSCs治疗COVID-19常用治疗方案注:MSCs为间充质干细胞;COVID-19为新型冠状病毒肺炎
表2 已完成MSCs治疗COVID-19的临床试验
参考文献 ID 国家 研究设计 纳入患者 患者例数 细胞来源
Monsel A (2022)[31] NCT04333368 法国 多中心、双盲、随机、安慰剂对照、2b期临床试验 ARDS 47 (治疗组:22;对照组:25) 脐带间充质干细胞
Wick KD (2021)[61] NCT02097641 美国 多中心、双盲、随机、安慰剂对照、2a期临床试验 ARDS(中度至重度) 27 (治疗组:17;对照组:10) 骨髓间充质干细胞
Zhu YG (2022)[17] NCT04276987 中国 单臂、开放标签、2a期临床试验 重型、危重型COVID-19 7 脂肪间充质干细胞外泌体
Lanzoni G (2021)[32] NCT04355728 美国 双盲、随机、1/2a期临床试验 ARDS 24 (治疗组:12;对照组:12) 脐带间充质干细胞
Kouroupis D (2021)[29] NA 美国 双盲、随机、1/2a期临床试验 ARDS 24 (治疗组:12;对照组:12) 脐带间充质干细胞
Grégoire, C. (2022)[39] NCT04445454 比利时 1/2期临床试验 重型、危重型COVID-19 8 骨髓间充质干细胞
Sadeghi, B. (2021)[37] IRCT2017010531786N1 伊朗 1/2期临床试验 ARDS 10 胎盘间充质干细胞
Fathi-Kazerooni M (2022)[21] NCT05019287 伊朗 随机、双盲、安慰剂对照、1/2期临床试验 ARDS 30 (治疗组:15;对照组:15) 间充质干细胞来源外泌体
Rebelatto CLK (2022)[28] U1111-1254-9819 巴西 1/2期,单中心,随机,双盲,安慰剂对照,临床试验 重型、危重型COVID-19 17 (治疗组:11;对照组:6) 脐带间充质干细胞
Bowdish, M. E. (2023)[20] NCT04371393 美国 多中心、随机、平行、双盲、安慰剂对照、3期临床试验 ARDS(中度至重度) 223 (治疗组:112;对照组:110) 骨髓间充质干细胞
Shi, L. (2021)[13] NCT04288102 中国 多中心、随机、双盲、安慰剂对照、2期临床试验 重型、危重型COVID-19 100 (治疗组:65;对照组:35) 脐带间充质干细胞
Saleh, M. (2021)[33] IRCT20190717044241N2 伊朗 单中心、开放标签、1期临床试验 重型、危重型COVID-19 5 脐带华通胶源间充质干细胞
Xu, X. (2021)[16] ChiCTR2000029606 中国 多中心、开放标签、非随机、平行对照1期临床实验 重型、危重型COVID19 44 (治疗组:26;对照组:18) 宫血间充质干细胞
参考文献 治疗方案 主要发现
Monsel A (2022)[31] 3×106/k,静脉输注,3次(day 1, 3, 5) 治疗组患者在D0和D7之间的PaO2/ fio2比值增幅较大;在治疗期间或之后(直至D28),重复输入UC-MSCs未伴发任何严重不良事件
Wick KD (2021)[61] 10 × 106/kg,单剂 气道标志物在MSC组和安慰剂组之间存在差异;Ang-2与无呼吸机天数(vfd)之间存在关联;气道RAGE与RALE之间存在关联
Zhu YG (2022)[17] haMSCsExos,(2.0 × 108 nano vesicles)连续使用5天 MSC外泌体未引起急性过敏或继发性过敏反应;MSC外泌体可促进肺部病变的吸收和缩短住院时间
Lanzoni G (2021)[32] (100±20) ×106,静脉输注,2次(D0和D3) UC-MSCs治疗COVID-19无治疗相关严重不良反应,是安全的;UC-MSCs治疗与参与COVID-19"细胞因子风暴"的一系列炎性细胞因子显著减少相关。UC-MSCs治疗与患者生存率和恢复时间显著改善相关
Kouroupis D (2021)[29] NA UC-MSC治疗6天后sTNFR2水平明显升高,TNFα和TNFβ水平降低
Grégoire, C. (2022)[39] 3×106 /kg,静脉输注,3次(day 0,3,6) MSC治疗COVID 19的安全性较好;能显著降低28天和60天重型COVID19患者的死亡率
Sadeghi, B. (2021)[37] 1×106 /kg,静脉输注,1~2次(第2次至少间隔3天) 胎盘来源蜕膜干细胞是安全的;能够改善COVID 19患者氧合水平,降低炎症因子水平,减少气管渗出
Fathi-Kazerooni M (2022)[21] 5mL MenSCs外泌体,5次(连续5天) MSC外泌体注射安全且耐受性良好;MSC外泌体注射改善缺氧,肺部受累,恢复免疫系统功能,控制细胞因子风暴
Rebelatto CLK (2022)[28] 5×105 /kg,静脉输注,3次(间隔48 h) 静脉注射3次UC-MSC后的安全性评价仅表现出轻微的AE,且与细胞输液无关;UC-MSCs在短时间内对患者的康复显示出有益的效果
Bowdish, M. E. (2023)[20] 2×106 /kg,静脉输注,2次(day 0, 4) 间充质细胞治疗安全性较好;未明显改善中重度COVID-19相关ARDS患者的30天生存率及60天内无呼吸机天数
Shi, L. (2021)[13] 4×107,静脉输注,3次(day1, 3, 6) UC-MSCs治疗能够促进肺实变的消退,对COVID-19肺损伤患者是一种安全且潜在有效的治疗方法
Saleh, M. (2021)[33] 150×106,静脉输注, 3次(day 1, 3, 6) MSC治疗可改善COVID-19患者的免疫功能,抑制炎症反应
Xu, X. (2021)[16] 3次共7×107,静脉输注,3次(day 1, 3, 5) 重症和危重型COVID-19患者的死亡率降低。
呼吸困难的症状得到改善,是重症和危重症患者可选的有效治疗方式
参考文献 ID 国家 研究设计 纳入患者 患者例数 细胞来源
Aghayan, H. R. (2022)[19] IRCT20200621047859N4 伊朗 非盲、1期临床 ARDS 20 (治疗组:10;对照组:10) 胎盘间充质干细胞
Meng F(2020)[12] NCT04252118 中国 非随机、开放标签、1期临床试验 COVID-19患者 18 (治疗组:9;对照组:9) 脐带间充质干细胞
Kaffash Farkhad N (2022)[22] IRCT20160809029275N1 伊朗 安慰剂对照、1期临床试验 COVID-19非重症ARDS. 20 (治疗组:10;对照组:10) 脐带间充质干细胞
Karyana M (2022)[23] NCT04535856 印度尼西亚 随机、双盲、安慰剂对照、1期临床试验 低危COVID-19. 9 DW间充质干细胞
O. Ercelen N (2021)[36] / 土耳其 临床试验 重型和危重型COVID19 210 (治疗组:99;对照组:111) 脐带间充质干细胞
Sengupta, V. (2020)[43] / 美国 单中心、非随机、开放标签、前瞻性队列研究 重型COVID19 27 骨髓间充质干细胞来源外泌体
Hashemian SR (2021)[38] none 伊朗 病例系列分析 ARDS 11 脐带/胎盘间充质干细胞
Chu M (2022)[11] ChiCTR2000030261 中国 探索性临床试验 COVID-19 46 (治疗组:7;对照组:39) 脐带间充质干细胞来源外泌体
Adas G (2021)[18] NCT04392778 土耳其 干预性、1/2期临床试验 ARDS(重度) 30 (治疗组:10;对照组:20) 脐带华通胶源间充质干细胞
Shu L (2020)[15] NA 中国 单中心、开放标签、随机对照临床试验 COVID-19 41 (治疗组:12;对照组:29) 脐带间充质干细胞
Dilogo IH (2021)[40] NCT04457609 印度尼西亚 多中心、双盲、随机对照临床试验 COVID-19 40 (治疗组:20;对照组:20) 脐带间充质干细胞
Leng Z (2020)[62] ChiCTR2000029990 中国 探索性临床试验 COVID-19 10 (治疗组:7;对照组:3) 间充质干细胞
Zarrabi M (2023)[63] IRCT20200217046526N2 伊朗 多中心随机对照临床试验 ARDS 43 (MSCs组:11;MSCs联合EVs:8;对照组:24) 间充质干细胞、外泌体
参考文献 治疗方案 主要发现
Aghayan, H. R. (2022)[19] 1 × 106/kg,静脉输注,1次 在COVID-19相关ARDS患者中静脉注射PL-MSCs是安全可行的
Meng F (2020)[12] 3 × 107,3次,静脉输注,3次(day 1,3,6) 输注UC-MSCs无严重不良事件发生。肺部病变在6天内得到良好控制,炎症细胞因子减少,PaO2/FiO2改善
Kaffash Farkhad N (2022)[22] 1×106/kg,静脉输注,3次(day 1,3,5) 细胞移植后无严重不良反应;SPO2/FIO2比值及血清CRP水平改善
Karyana M (2022)[23] 5×107/10×107,静脉输注,1次 输注期间和输注24 h后没有发生治疗相关不良事件;患者存活率为100%,3组之间的临床结果无明显差异
O. Ercelen N (2021)[36] (1 ~ 2)×106/kg,静脉输注,1次 UC-MSC治疗是安全的,有很大的潜力被用作COVID-19重症患者的治疗方法
Sengupta, V. (2020)[43] 静脉输注,1次 骨髓间充质干细胞来源外泌体安全性较好,并能够恢复氧合功能、下调细胞因子、发挥免疫功能,是重型COVID19的有效治疗方式
Hashemian SR (2021)[38] 200 × 106 cells隔日 MSCs治疗可显著降低重型COVID-19患者炎症因子水平
Chu M (2022)[11] 5 mL (浓度7.66e + 0.8 to 7.00e + 0.7 particles/mL),雾化吸入,2次/天(8:30,16:00,每次10分钟) 针对轻症COVID-19肺炎病例,雾化msc来源的外泌体未引起急性或继发性过敏反应,但可促进肺部病变的吸收和缩短住院时间
Adas G (2021)[18] 1×106/kg,静脉输注,3次(day 1,2,3) 抑制了细胞因子风暴并减缓了疾病进展。MSC介导的生长和分化减少了对受损器官的损伤,加速了受损器官的恢复。降低了死亡率,减少了ICU住院时间,并且具有良好的安全性
Shu L (2020)[15] 1×106/kg,静脉输注 显著降低了COVID-19患者的疾病进展及死亡率;症状改善时间缩短,C反应蛋白和IL-6降低,肺部炎症改善时间缩短
Dilogo IH (2021)[40] 1×106/kg,静脉输注 治疗组患者生存率显著提高,IL-6水平显著降低;无治疗相关严重不良反应
Leng Z (2020)[62] 1×106 /kg,静脉输注,1次 MSCs治疗可改善COVID-19患者的预后;可能机制是MSCs可调节炎症反应,促进组织修复和再生
Zarrabi M (2023)[63] MSCs:(100 × 106)±10%、EVs:(100× 106)±10%分泌,静脉输注,2次(间隔48 h) MSCs联合MSCs源性EVs安全可耐受;可有效改善ARDS患者细胞因子风暴
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