Journal of Peking University(Health Sciences) ›› 2018, Vol. 50 ›› Issue (6): 1014-1021. doi: 10.19723/j.issn.1671-167X.2018.06.013

• Article • Previous Articles     Next Articles

Efficacy of mesenchymal stem cells on systemic lupus erythematosus:a meta-analysis

Shuang LIU1,Yu-long GUO2,Jing-yi YANG3,Wei WANG1,Jian XU1,()   

  1. 1. Department of Rheumatology and Immunology, First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
    2. Department of Cardiology, Yunnan Provincial Fuwai Cardiovascular Disease Hospital, Kunming 650000, China
    3. Yunnan Shunxi Regeneration Medical Engineering Co., Ltd, Kunming 650000, China
  • Received:2018-07-10 Online:2018-12-18 Published:2018-12-18
  • Contact: Jian XU E-mail:casxujian@163.com
  • Supported by:
    Supported by the National Natural Science Foundation of China(81160379);Supported by the National Natural Science Foundation of China(81460256);Supported by the National Natural Science Foundation of China(81560233);Supported by the National Natural Science Foundation of China(81501406);Supported by the National Natural Science Foundation of China(81760296);Yunnan Applied Basic Research Projects-Union Foundation(2017FE467);Yunnan Applied Basic Research Projects-Union Foundation(2017FE467(-138));the Funding of Yunnan Provincial Health Science and Technology Plan(2014NS171);the Funding of Yunnan Provincial Health Science and Technology Plan(2016NS026);the Funding of Yunnan Provincial Health Science and Technology Plan(2016NS052);the Funding of Yunnan Provincial Health Science and Technology Plan(2017NS051);the Funding of Yunnan Provincial Health Science and Technology Plan(2018NS0133);the Funding of Yunnan Provincial Health Science and Technology Plan(2018NS0134);Yunnan Provincial Fund for High Level Reserve Talents in Health Science(H-2017068);Yunnan Provincial Fund for Preparatory Young Leaders in Academic and Technology(2015HB071);Yunnan Provincial Fund for Preparatory Young Leaders in Academic and Technology (2015HB071), the Hundred-Talent Program of Kunming Medical University(60117190457);Innovative Research Team of Kunming Medical University(CXTD201613)

Abstract:

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and several typical autoantibodies. Mesenchymal stem cells (MSC) are multipotent stem cells with low immunogenicity that can differentiate into various kinds of cells, such as bone, cartilage, fat and skin tissue. MSC have immunomodulatory and reparative properties through interactions with immune cells. MSC have been used in the treatment of refractory SLE and lupus nephritis patients for more than ten years. Most clinical studies were self-controlled studies and only a few were randomized controlled trials. The objective of this study was to use meta-analysis method to evaluate the efficacy and safety of MSC treatment in SLE patients. Methods:The PubMed, Cochrane Library, Wanfang and VIP databases were searched for published randomized controlled trials and self-controlled studies before June 1, 2018. The search terms included the Chinese and English versions of mesenchymal stem cells, Mesenchymal Stromal Cells [Mesh], systemic lupus erythematosus, lupus, Lupus Erythematosus, Systemic [Mesh]. Two authors independently screened the literatures, assessed the quality of the studies and collected data according to the inclusion and exclusion criteria. The endpoints were the SLE disease activity index, 24 h urine protein and complement C3. Meta-analysis was performed with the Revman 5.3 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard. Results:Eight studies involving 213 patients were included and three of the studies were randomized controlled trials with 66 patients involved. The MSC group showed that the SLE disease activity index decreased significantly [standard mean difference (SMD)=-1.76, 95% confidence interval (CI):-2.00 to -1.51, P<0.001), the 24 h urine protein decreased significantly (SMD=-1.74, 95%CI:-2.46 to -1.03, P<0.001), as well as the complement C3 increased significantly (SMD=1.28, 95%CI: 0.93 to 1.62, P<0.001). Four studies reported adverse events including fever, diarrhea and headache during the infusion. Conclusion:Current evidences showed that MSC could improve the disease activity, proteinuria and hypocomplementemia in SLE patients. Large scale and high-quality randomized controlled trials are required to validate the efficacy and safety of MSC treatment in SLE patients.

Key words: Mesenchymal stem cell, Systemic lupus erythematosus, Lupus nephritis, Meta-analysis

CLC Number: 

  • R593.24

Figure 1

Flow of study selection"

Table 1

Table A summary of the included eight studies"

Table 2

Quality assessment of randomized controlled trials"

Table 3

Quality assessment of self-control studies"

Study Representativeness of the exposed cohort Selection
of the non-
exposed cohort
Ascertainment of
exposure
Demonstration that the outcome of
interest was
not present
at baseline
Comparability of cohorts on the basis of design or analysis Assessment of the out-
come
Was follow-up enough
for outcomes
to occur?
Adequacy of
follow-up of
cohorts
Gu, et al, 2014[15] Yes NA Yes Yes NA Yes Yes Yes
Zhu, et al, 2016[17] Yes NA Yes Yes NA Yes No Yes
Li, et al, 2016[13] Yes NA Yes Yes NA Yes Yes Yes
Qiu, et al, 2016[18] Yes NA Yes Yes NA Yes Yes Yes
Bai, et al, 2017[12] Yes NA Yes Yes NA Yes Yes Yes

Figure 2

Summary of meta-analysis for SLEDAI outcomesRCT, randomized controlled trial;SD, standard deviation;CI, confidence interval;SLEDAI, systemic lupus erythematosus disease activity index."

Figure 3

Summary of meta-analysis for urine protein outcomesAbbreviations as in Figure 2."

Figure 4

Summary of meta-analysis for complement outcomesAbbreviations as in Figure 2."

[1] 中华医学会风湿病学分会. 系统性红斑狼疮诊断及治疗指南[J]. 中华风湿病学杂志, 2010,14(5):342-346.
[2] van Vollenhoven RF, Mosca M, Bertsias G , et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force[J]. Ann Rheum Dis, 2014,73(6):958-967.
doi: 10.1136/annrheumdis-2013-205139 pmid: 24739325
[3] He J, Zhang X, Wei Y , et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus[J]. Nat Med, 2016,22(9):991-993.
doi: 10.1038/nm.4148 pmid: 27500725
[4] 王丹丹, 孙凌云 . 间充质干细胞移植治疗重症自身免疫病[J]. 中国实用内科杂志, 2015,35(10):831-834.
[5] 梁军, 孙凌云 . 间充质干细胞治疗系统性红斑狼疮的基础和临床研究[J]. 浙江医学, 2017,39(21):1836-1841.
[6] Carrion F, Nova E, Ruiz C , et al. Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupuserythematosus patients[J]. Lupus, 2010,19(3):317-322.
doi: 10.1177/0961203309348983
[7] Deng D, Zhang P, Guo Y , et al. A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis[J]. Ann RheumDis, 2017,76(8):1436-1439.
doi: 10.1136/annrheumdis-2017-211073
[8] Hochberg MC . Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus[J]. Arthritis Rheum, 1997,40(9):1725.
[9] Petri M, Orbai A, Alarcón GS , et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus[J]. Arthritis Rheum, 2012,64(8):2677-2686.
doi: 10.1002/art.34473
[10] Gladman DD, Iba ED, Urowitz MB . Systemic lupus erythematosus disease activity index 2000[J]. J Rheumatol, 2002,29(2):288-291.
doi: 10.1097/00124743-200202000-00018 pmid: 11838846
[11] 杨桂鲜, 潘丽萍, 陈志琴 , 等. 脐带间充质干细胞移植治疗狼疮性肾炎的临床疗效[J]. 实用医学杂志, 2014,30(17):2779-2781.
doi: 10.3969/j.issn.1006-5725.2014.17.029
[12] 白茹, 戚燕, 吕昭萍 , 等. 脐带间充质干细胞移植治疗难治性系统性红斑狼疮3年随访[J]. 中国免疫学杂志, 2017,33(6):905-909.
doi: 10.3969/j.issn.1000-484X.2017.06.020
[13] 李俊霞, 林强, 陈建 , 等. 脐带间充质干细胞对增殖型狼疮性肾炎的临床疗效观察[J]. 中华细胞与干细胞杂志: 电子版, 2016,6(3):174-178.
doi: 10.3877/cma.j.issn.2095-1221.2016.03.007
[14] 唐帮丽, 邓丹琪, 张佩莲 , 等. 脐带间充质干细胞移植治疗狼疮性肾炎的疗效与机制[J]. 昆明医科大学学报, 2016,37(7):93-98.
doi: 10.3969/j.issn.1003-4706.2016.07.022
[15] Gu F, Wang D, Zhang H , et al. Allogeneic mesenchymal stem cell transplantation for lupus nephritis patients refractory to conventional therapy[J]. Clin Rheumatol, 2014,33(11):1611-1619.
doi: 10.1007/s10067-014-2754-4 pmid: 25119864
[16] 曾雯, 胡英, 杨霞 , 等. 间充质干细胞联合吗替麦考酚酯治疗狼疮性肾炎的临床效果[J]. 中国当代医药, 2016,23(7):67-70.
[17] 朱宁, 毛静, 张小莲 , 等. 脐带间充质干细胞移植在系统性红斑狼疮患者中的应用研究[J]. 疑难病杂志, 2016,15(1):44-47.
doi: 10.3969/j.issn.1671-6450.2016.01.011
[18] 裘影影, 何建强, 汤郁 , 等. 脐带间充质干细胞移植治疗难治性系统性红斑狼疮患者的疗效分析[J]. 中国实用医药, 2016,11(25):68-69.
[19] Sun L, Akiyama K, Zhang H , et al. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans[J]. Stem Cells, 2009,27(6):1421-1432.
doi: 10.1002/stem.68 pmid: 19489103
[20] 杨桂鲜, 潘丽萍, 曹礼应 , 等. 脐带间充质干细胞治疗难治性系统性红斑狼疮的临床研究[J]. 云南医药, 2018,39(1):38-41.
[21] 杨桂鲜, 潘丽萍, 陈志琴 , 等. 脐带间充质干细胞治疗系统性红斑狼疮的量效关系[J]. 云南医药, 2015,36(6):579-584.
[22] 杨桂鲜, 潘丽萍, 宋薇 , 等. 脐带间充质干细胞治疗难治性系统性红斑狼疮临床分析[J]. 实用医学杂志, 2014,30(5):735-738.
doi: 10.3969/j.issn.1006-5725.2014.05.019
[23] 杨桂鲜, 潘丽萍, 周巧艳 , 等. 脐带间充质干细胞移植辅助治疗系统性红斑狼疮的疗效观察[J]. 四川大学学报(医学版), 2014,45(2):338-341.
[24] Klimczak A, Kozlowska U . Mesenchymal stromal cells and tissue-specific progenitor cells: their role in tissue homeostasis[J]. Stem Cells Int, 2016,4285215. doi: 10.1155/2016/4285215.
doi: 10.1155/2016/4285215 pmid: 4707334
[25] Sun LY, Zhang HY, Feng XB , et al. Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus[J]. Lupus, 2007,16(2):121-128.
doi: 10.1177/0961203306075793
[26] Nie Y, Lau C, Lie A , et al. Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus[J]. Lupus, 2010,19(7):850-859.
doi: 10.1177/0961203310361482 pmid: 20118163
[27] Li X, Liu L, Meng D , et al. Enhanced apoptosis and senescence of bone-marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus[J]. Stem Cells Dev, 2012,21(13):2387-2394.
doi: 10.1089/scd.2011.0447 pmid: 22375903
[28] Gu Z, Tan W, Feng G , et al. Wnt/beta-catenin signaling me-diates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients through the p53/p21 pathway[J]. Mol Cell Biochem, 2014,387(1-2):27-37.
doi: 10.1007/s11010-013-1866-5 pmid: 24130040
[29] Wang D, Feng X, Lu L , et al. A CD8 T cell/indoleamine 2, 3-dioxygenase axis is required for mesenchymal stem cell suppression of human systemic lupus erythematosus[J]. Arthritis Rheum, 2014,66(8):2234-2245.
doi: 10.1002/art.38674 pmid: 24756936
[30] Feng X, Che N, Liu Y , et al. Restored immunosuppressive effect of mesenchymal stem cells on B cells after olfactory 1/early B cell factor-associated zinc-finger protein down-regulation in patients with systemic lupus erythematosus[J]. Arthritis Rheum, 2014,66(12):3413-3423.
doi: 10.1002/art.v66.12
[31] Fathollahi A, Gabalou NB, Aslani S . Mesenchymal stem cell transplantation in systemic lupus erythematous, a mesenchymal stem cell disorder[J]. Lupus, 2018,27(7):1053-1064.
doi: 10.1177/0961203318768889
[32] Choi EW, Shin IS, Park SY , et al. Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation[J]. Arthritis Rheum, 2012,64(1):243-253.
doi: 10.1002/art.33313 pmid: 21904997
[33] Choi EW, Lee M, Song JW , et al. Mesenchymal stem cell transplantation can restore lupus disease-associated miRNA expression and Th1/Th2 ratios in a murine model of SLE[J]. Sci Rep, 2016(6):38237.
doi: 10.1038/srep38237 pmid: 27924862
[34] Zhou K, Zhang H, Jin O , et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice[J]. Cell Mol Immunol, 2008,5(6):417-424.
doi: 10.1038/cmi.2008.52
[35] Tang Y, Xie H, Chen J , et al. Activated NF-kappaB in bone marrow mesenchymal stem cells from systemic lupus erythematosus patients inhibits osteogenic differentiation through downregulating Smad signaling[J]. Stem Cells Dev, 2013,22(4):668-678.
doi: 10.1089/scd.2012.0226
[36] Sun L, Wang D, Liang J , et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus[J]. Arthritis Rheum, 2010,62(8):2467-2475.
doi: 10.1002/art.v62:8
[37] Zhang Z, Feng R, Niu L , et al. Humanumbilical cord mesenchymal stem cells inhibit T follicular helper cell expansion through the activation of iNOS in lupus-prone B6.MRL-Fas(lpr) mice[J]. Cell Transplant, 2017,26(6):1031-1042.
doi: 10.3727/096368917X694660 pmid: 28105982
[38] Deng W, Chen W, Zhang Z , et al. Mesenchymal stem cells promote CD206 expression and phagocytic activity of macrophages through IL-6 in systemic lupus erythematosus[J]. Clin Immunol, 2015,161(2):209-216.
doi: 10.1016/j.clim.2015.07.011 pmid: 26209923
[39] Che N, Li X, Zhou S , et al. Umbilical cord mesenchymal stem cells suppress B-cell proliferation and differentiation[J]. Cell Immunol, 2012,274(1-2):46-53.
doi: 10.1016/j.cellimm.2012.02.004 pmid: 22414555
[40] Le Blanc K, Ringden O . Immunomodulation by mesenchymal stem cells andclinical experience[J]. J Intern Med, 2007,262(5):509-525.
doi: 10.1016/j.placenta.2011.07.035 pmid: 17949362
[41] Chamberlain G, Fox J, Ashton B , et al. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing[J]. Stem Cells, 2007,25(11):2739-2749.
doi: 10.1634/stemcells.2007-0197
[42] Alunno A, Bistoni O, Montanucci P , et al. Umbilical cord mesenchymal stem cells for the treatment of autoimmune diseases: beware of cell-to-cell contact[J]. Ann RheumDis, 2018,77(3):e14.
doi: 10.1136/annrheumdis-2017-211790 pmid: 28611081
[43] Lalu MM, Mcintyre L, Pugliese C , et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials[J]. PLoS One, 2012,7(10):e47559.
doi: 10.1371/journal.pone.0047559
[44] 汤郁, 雷芳, 宋东明 , 等. 脐带间充质干细胞治疗结缔组织病不良反应分析[J]. 南京医科大学学报(自然科学版), 2014,34(12):1687-1689.
[1] Jia-yi TIAN,Xia ZHANG,Gong CHENG,Qing-hong LIU,Shi-yang WANG,Jing HE. Serum interleukin-2 receptor α as a clinical biomarker in patients with systemic lupus erythematosus [J]. Journal of Peking University (Health Sciences), 2021, 53(6): 1083-1087.
[2] Jian-mei ZOU,Li-jun WU,Cai-nan LUO,Ya-mei SHI,Xue WU. Relationship of serum 25- hydroxy vitamin D and systemic lupus erythematosus [J]. Journal of Peking University (Health Sciences), 2021, 53(5): 938-941.
[3] YOU Peng-yue,LIU Yu-hua,WANG Xin-zhi,WANG Si-wen,TANG Lin. Biocompatibility and effect on bone formation of a native acellular porcine pericardium: Results of in vitro and in vivo [J]. Journal of Peking University (Health Sciences), 2021, 53(4): 776-784.
[4] XIA Fang-fang,LU Fu-ai,LV Hui-min,YANG Guo-an,LIU Yuan. Clinical characteristics and related factors of systemic lupus erythematosus with interstitial pneumonia [J]. Journal of Peking University (Health Sciences), 2021, 53(2): 266-272.
[5] FENG Jing-nan,GAO Le,SUN Yi-xin,YANG Ji-chun,DENG Si-wei,SUN Feng,ZHAN Si-yan. Accuracy of Xpert®MTB/RIF for the detection of tuberculosis and rifampicin-resistance tuberculosis in China: A systematic review and meta-analysis [J]. Journal of Peking University (Health Sciences), 2021, 53(2): 320-326.
[6] Bao-qi ZENG,Shu-qing YU,Yao CHEN,Wei ZHAI,Bin LIU,Si-yan ZHAN,Feng SUN. Safety of biological valves for aortic valve replacement: A systematic review and meta-analysis [J]. Journal of Peking University (Health Sciences), 2020, 52(3): 547-556.
[7] Xiang-song BAI,Long-wei LV,Yong-sheng ZHOU. Tribbles pseudokinase 3 inhibits the adipogenic differentiation of human adipose-derived mesenchymal stem cells [J]. Journal of Peking University(Health Sciences), 2020, 52(1): 1-9.
[8] Yan GENG,Bo-rui LI,Zhuo-li ZHANG. Musculoskeletal ultrasound findings of symptomatic joints in patients with systemic lupus erythematosus [J]. Journal of Peking University(Health Sciences), 2020, 52(1): 163-168.
[9] Ying-ni LI,Xiao-hong XIANG,Jing ZHAO,Yun LI,Feng SUN,Hong-yan WANG,Ru-lin JIA,Fan-lei HU. Significance of anti-carbamylated fibrinogen antibodies in systemic lupus erythematosus [J]. Journal of Peking University(Health Sciences), 2019, 51(6): 1019-1024.
[10] Yu-hua WANG,Guo-hua ZHANG,Ling-ling ZHANG,Jun-li LUO,Lan GAO. Adrenal hemorrhage in a patient with systemic lupus erythematosus [J]. Journal of Peking University(Health Sciences), 2019, 51(6): 1178-1181.
[11] Jing XIE,Yu-ming ZHAO,Nan-quan RAO,Xiao-tong WANG,Teng-jiao-zi FANG,Xiao-xia LI,Yue ZHAI,Jing-zhi LI,Li-hong GE,Yuan-yuan WANG. Comparative study of differentiation potential of mesenchymal stem cells derived from orofacial system into vascular endothelial cells [J]. Journal of Peking University(Health Sciences), 2019, 51(5): 900-906.
[12] Ying WANG,Ming-hui LI,Yan ZHANG,Xiao-yan HU,Rui-xia MA. Relationship between podocyte injury and macrophage infiltration in renal tissues of patients with lupus nephritis [J]. Journal of Peking University(Health Sciences), 2019, 51(4): 723-727.
[13] Yi-ran ZHANG,Feng RAO,Wei PI,Pei-xun ZHANG,Bao-guo JIANG. Proximal femoral nails antirotation and dynamic hip screws for fixation of unstable intertrochanteric fractures of femur: A meta-analysis [J]. Journal of Peking University(Health Sciences), 2019, 51(3): 493-500.
[14] Xia LIU,Ying ni LI,Xiao li SUN,Qing lin PENG,Xin LU,Guo chun WANG. Effects of integrin metalloproteinases on osteogenic differentiation [J]. Journal of Peking University(Health Sciences), 2018, 50(6): 962-967.
[15] Xiao-hui ZHANG,Xue-rong DENG,Fan Li,Ying ZHU,Zhuo-li ZHANG. Posterior reversible encephalopathy syndrome in systemic lupus erythematosus: a case report [J]. Journal of Peking University(Health Sciences), 2018, 50(6): 1102-1107.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] . [J]. Journal of Peking University(Health Sciences), 2009, 41(4): 456 -458 .
[2] . [J]. Journal of Peking University(Health Sciences), 2009, 41(2): 125 -128 .
[3] . [J]. Journal of Peking University(Health Sciences), 2009, 41(2): 135 -140 .
[4] . [J]. Journal of Peking University(Health Sciences), 2009, 41(2): 158 -161 .
[5] . [J]. Journal of Peking University(Health Sciences), 2009, 41(2): 217 -220 .
[6] . [J]. Journal of Peking University(Health Sciences), 2009, 41(1): 52 -55 .
[7] . [J]. Journal of Peking University(Health Sciences), 2009, 41(1): 109 -111 .
[8] . [J]. Journal of Peking University(Health Sciences), 2009, 41(3): 297 -301 .
[9] . [J]. Journal of Peking University(Health Sciences), 2009, 41(5): 505 -515 .
[10] . [J]. Journal of Peking University(Health Sciences), 2009, 41(5): 599 -601 .