Application of mesenchymal stem cells in regulating immune function of patients with coronavirus disease-2019

doi:10.3877/cma.j.issn.2096-1537.2021.01.010

Abstract

Abstract:

Coronavirus disease-2019(COVID-19) is a potentially fatal infectious disease. COVID-19 can seriously damage the immune system, leading to the over-activation of immune cells, so that a large number of inflammatory cytokines are released, forming cytokine storm, thereby exacerbating tissue damage and disease development. To effectively control inflammatory storm has become a key point in the treatment of patients with COVID-19. Mesenchymal stem cells (MSCs) can effectively control abnormal immune response and inhibit damage to multiple human organs due to the virtue of low immunogenicity and regulating ability to both innate and adaptive immunity. According to the characteristics of immune dysfunction in COVID-19 patients and previous studies, MSCs may have a good effect on treatment of COVID-19. This article focuses on analyzing changes of innate and adaptive immune responses in COVID-19 patients and elucidates the regulation mechanism of MSCs on immunity, in order to provide new insights and theory for clinical immunotherapy in COVID-19 patients.

Key words: Coronavirus disease-2019, Immune function, Mesenchymal stem cells

Kun Lu, Shitao Geng, Jing Xia, Shikai Tang, Wei Zhang, Haiying Wu, Chuanyun Qian. Application of mesenchymal stem cells in regulating immune function of patients with coronavirus disease-2019[J]. Chinese Journal of Critical Care & Intensive Care Medicine(Electronic Edition), 2021, 07(01): 55-65.

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URL: https://icu.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2096-1537.2021.01.010

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References 101

1	Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China [J]. Nature, 2020, 579(7798): 265-269.
2	Gorbalenya AE, Baker SC, Baric RS, et al. Severe acute respiratory syndrome-related coronavirus: the species and its viruses--a statement of the Coronavirus Study Group [EB/OL]. (2020-02-11) [2020-06-15]. URL
3	Wan Y, Shang J, Graham R, et al. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus [J]. J Virol, 2020, 94(7): e00127-20.
4	高钰琪. 基于新冠肺炎病理生理机制的治疗策略 [J]. 中国病理生理杂志, 2020, 36(3): 568-572, 576.
5	Li G, He X, Zhang L, et al. Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19 [J]. J Autoimmun, 2020, 102463. (2020-04-13) [2020-06-15]. URL
6	Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019 [J]. J Clin Invest, 2020, 130(5): 2620‐2629.
7	Ivashkiv LB, Donlin LT. Regulation of type I interferon responses [J]. Nat Rev Immunol, 2014, 14(1): 36-49.
8	Li G, Fan Y, Lai Y, et al. Coronavirus infections and immune responses [J]. J Med Virol, 2020, 92(4): 424-432.
9	Zinkernagel RM. Immunology taught by viruses [J]. Science, 1996, 271(5246): 173‐178.
10	Larsson M, Messmer D, Somersan S, et al. Requirement of mature dendritic cells for efficient activation of influenza A-specific memory CD8⁺T cells [J]. J Immunol, 2000, 165(3): 1182-1190.
11	Belz GT, Smith CM, Kleinert L, et al. Distinct migrating and nonmigrating dendritic cell population are involved in MHC class I-restricted antigen presentation after lung infection with virus [J]. Proc Natl Acad Sci U S A, 2004, 101(23): 8670-8675.
12	Channappanavar R, Zhao J, Perlman S. T cell-mediated immune response to respiratory coronaviruses [J]. Immunol Res, 2014, 59(1-3): 118-128.
13	Saha B, Jyothi Prasanna S, Chandrasekar B, et al. Gene modulation and immunoregulatory roles of interferon γ [J]. Cytokine, 2010, 50(1): 1-14.
14	Román E, Miller E, Harmsen A, et al. CD4 effector T cell subsets in the response to influenza: heterogeneity, migration, and function [J]. J Exp Med, 2002, 196(7): 957-968.
15	Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China [EB/OL]. Clin Infect Dis, 2020, ciaa248. (2020-04-12) [2020-06-15]. URL
16	Giamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure [J]. Cell Host Microbe, 2020, 27(6): 992‐1000.
17	Tufan A, Avanoğlu Güler A, Matucci-Cerinic M. COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs [J]. Turk J Med Sci, 2020, 50(SI-1): 620‐632.
18	Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China [J]. JAMA, 2020, 323(11): 1061‐1069.
19	Lin L, Lu L, Cao W, et al. Hypothesis for potential pathogenesis of SARS- CoV-2 infection- a review of immune changes in patients with viral pneumonia [J]. Emerg Microbes Infect, 2020, 9(1): 727‐732.
20	Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury [J]. Sci China Life Sci, 2020, 63(3): 364‐374.
21	Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome [J]. Lancet Respir Med, 2020, 2600(20): 19-21.
22	Rockx B, Baas T, Zornetzer GA, et al. Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection [J]. J Virol, 2009, 83(14): 7062‐7074.
23	He L, Ding Y, Zhang Q, et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS [J]. J Pathol, 2006, 210(3): 288‐297.
24	Fischer DD, Kandasamy S, Paim FC, et al. Protein malnutrition alters tryptophan and angiotensin-converting enzyme 2 homeostasis and adaptive immune responses in human rotavirus-infected gnotobiotic pigs with human infant fecal microbiota transplant [J]. Clin Vaccine Immunol, 2017, 24(8): e00172.
25	Zhu H, Rhee JW, Cheng P, et al. Cardiovascular complications in patients with COVID-19: consequences of viral toxicities and host immune response [J]. Curr Cardiol Rep, 2020, 22(5): 32.
26	Nelemans T, Kikkert M. Viral innate immune evasion and the pathogenesis of emerging RNA virus infections [J]. Viruses, 2019, 11(10): 961.
27	Fehr AR, Channappanavar R, Perlman S. Middle East respiratory syndrome: emergence of a pathogenic human coronavirus [J]. Annu Rev Med, 2017, 68: 387‐399.
28	Newton AH, Cardani A, Braciale TJ. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology [J]. Semin immunopathol, 2016 , 38(4): 471-482.
29	Totura AL, Baric RS. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon [J]. Curr Opin Virol, 2012, 2(3): 264-275.
30	Moore JB, June CH. Cytokine release syndrome in severe COVID-19 [J]. Science, 2020, 368(6490): 473‐474.
31	Chu H, Zhou J, Wong BH, et al. Middle East respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways [J]. J Infect Dis, 2016, 213(6): 904‐914.
32	Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients [J]. Cell Mol Immunol, 2020, 17(5): 533‐535.
33	Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China [EB/OL]. JAMA Intern Med, 2020, e200994. (2020-03-13) [2020-06-15]. URL
34	Neurath MF. Covid-19 and immunomodulation in IBD [J]. Gut, 2020, 69(7): 1335‐1342.
35	Sun D, Li H, Lu XX, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study [J]. World J Pediatr, 2020, 16(3): 251-259.
36	Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China [J]. N Engl J Med, 2020, 382(18): 1708‐1720.
37	Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [J]. Lancet, 2020, 395(10223): 497-506.
38	Kong SL, Chui P, Lim B, et al. Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients [J]. Virus Res, 2009, 145(2): 260-269.
39	Fong PC, Boss DS, ap TAY, et al. A novel coronavirus associated with severe acute respiratory syndrome [J]. N Engl J Med, 2009, 361(2): 123-134.
40	Baas T, Taubenberger J, Chong P, et al. SARS-CoV virus-host interactions and comparative etiologies of acute respiratory distress syndrome as determined by transcriptional and cytokine profiling of formalin-fixed paraffin-embedded tissues [J]. J Interf Cytokines Res, 2006, 26(5): 309-317.
41	Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice [J]. Cell Host Microbe, 2016, 19(2): 181‐193.
42	Dong N, Yang X, Ye L, et al. Genomic and protein structure modelling analysis depicts the origin and infectivity of 2019-nCoV, a new coronavirus which caused a pneumonia outbreak in Wuhan, China[EB/OL]. BioRxiv, 2020. URL
43	Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation [J]. Science, 2020, 367(6483): 1260-1263.
44	Wang F, Nie J, Wang H, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia [J]. J Infect Dis, 2020, 221(11): 1762‐1769.
45	Wang W, He J, Lie P, et al. The definition and risks of cytokine release syndrome-like in 11 COVID-19-infected pneumonia critically ill patients: disease characteristics and retrospective analysis [J]. MedRxiv, 2020.
46	Wan S, Yi Q, Fan S, et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP) [J]. MedRxiv, 2020.
47	Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib [J]. J Microbiol Immunol Infect, 2020, S1684-1182(20)30065-7.
48	Hoe E, Anderson J, Nathanielsz J, et al. The contrasting roles of Th17 immunity in human health and disease [J]. Microbiol Immunol, 2017, 61(2): 49‐56.
49	Murdock BJ, Falkowski NR, Shreiner AB, et al. Interleukin-17 drives pulmonary eosinophilia following repeated exposure to Aspergillus fumigatus conidia [J]. Infect Immun, 2012, 80(4): 1424‐1436.
50	Hotez PJ, Bottazzi ME, Corry DB. The potential role of Th17 immune responses in coronavirus immunopathology and vaccine-induced immune enhancement [J]. Microbes Infect, 2020, 22(4): 165‐167.
51	Chen G, Wu D, Guo W, et al. Clinical and immunologic features in severe and moderate forms of coronavirus disease 2019 [J]. medRxiv, 2020, 2020.02.16.20023903.
52	Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance [J]. Cell, 2008, 133(5): 775-787.
53	Sakaguchi S, Miyara M, Costantino CM, et al. FOXP3+ regulatory T cells in the human immune system [J]. Nat Rev Immunol, 2010, 10(7): 490-500.
54	Diao B, Wang C, Tan Y, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19) [J]. Front Immunol, 2020, 11: 827.
55	Cao Z, Liu L, Du L, et al. Potent and persistent antibody responses against the receptor-binding domain of SARS-CoV spike protein in recovered patients [J]. Virol J, 2010, 7: 299.
56	Xu B, Fan CY, Wang AL, et al. Suppressed T cell-mediated immunity in patients with COVID-19: A clinical retrospective study in Wuhan, China [J]. J Infect, 2020, S0163-4453(20)30223-1.
57	Qu W, Wang Z, Hare JM, et al. Cell-based therapy to reduce mortality from COVID-19: Systematic review and meta-analysis of human studies on acute respiratory distress syndrome [J]. Stem Cells Transl Med, 2020, 10.1002/sctm.20-0146.
58	Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2^- mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia [J]. Aging Dis, 2020, 11(2): 216-228.
59	Liang B, Chen J, Li T, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord [J]. Medicine (Baltimore), 2020, 99(31): e21429.
60	Bari E, Ferrarotti I, Saracino L, et al. Mesenchymal stromal cell secretome for severe COVID-19 infections: premises for the therapeutic use [J]. Cells, 2020, 9(4): 924.
61	Xiong J, Bao L, Qi H, et al. Mesenchymal stem cell-based therapy for COVID-19: possibility and potential [J]. Curr Stem Cell Res Ther, 2020, 10.2174/1574888X15666200601152832.
62	Metcalfe SM. Mesenchymal stem cells and management of COVID-19 pneumonia [J]. Med Drug Discov, 2020, 5: 100019.
63	Liu S, Peng D, Qiu H, et al. Mesenchymal stem cells as a potential therapy for COVID-19 [J]. Stem Cell Res Ther, 2020, 11(1): 169.
64	Rajarshi K, Chatterjee A, Ray S. Combating COVID-19 with mesenchymal stem cell therapy [J]. Biotechnol Rep (Amst), 2020, 26: e00467.
65	Qi K, Li N, Zhang Z, et al. Tissue regeneration: the crosstalk between mesenchymal stem cells and immune response [J]. Cell Immunol, 2018, 326: 86‐93.
66	Naik S, Larsen SB, Cowley CJ, et al. Two to tango: dialog between immunity and stem cells in health and disease [J]. Cell, 2018, 175(4): 908‐920.
67	Razmkhah M, Abtahi S, Ghaderi A. Mesenchymal stem cells, immune cells and tumor cells crosstalk: a sinister triangle in the tumor microenvironment [J]. Curr Stem Cell Res Ther, 2019, 14(1): 43‐51.
68	郑盛, 杨涓, 唐映梅. 间充质干细胞在炎症免疫调节中的作用及应用进展 [J]. 中国组织工程研究, 2015, 19(45): 7362-7368.
69	Luu NT, McGettrick HM, Buckley CD, et al. Crosstalk between mesenchymal stem cells and endothelial cells leads to downregulation of cytokine-induced leukocyte recruitment [J]. Stem Cells, 2013, 31(12): 2690‐2702.
70	Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system [J]. Nat Rev Immunol, 2012, 12(5): 383-396.
71	Cho KA, Lee JK, Kim YH, et al. Mesenchymal stem cells ameliorate B-cell-mediated immune responses and increase IL-10-expressing regulatory B cells in an EBI3-dependent manner [J]. Cell Mol Immunol, 2017, 14(11): 895‐908.
72	Wang D, Li SP, Fu JS, et al. Resveratrol augments therapeutic efficiency of mouse bone marrow mesenchymal stem cell-based therapy in experimental autoimmune encephalomyelitis [J]. Int J Dev Neurosci, 2016, 49: 60‐66.
73	Contreras RA, Figueroa FE, Djouad F, et al. Mesenchymal stem cells regulate the innate and adaptive immune responses dampening arthritis progression [J]. Stem Cells Int, 2016, 2016: 3162743.
74	Shetty AK. Mesenchymal stem cell infusion shows promise for combating coronavirus (COVID-19)-induced pneumonia [J]. Aging Dis, 2020, 11(2): 462-464.
75	Rogers CJ, Harman RJ, Bunnell BA, et al. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients [J]. J Transl Med, 2020, 18(1): 203.
76	Ji F, Li L, Li Z, et al. Mesenchymal stem cells as a potential treatment for critically ill patients with coronavirus disease 2019 [J]. Stem Cells Transl Med, 2020, 9(7): 813-814.
77	Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor [J]. Cell, 2020, 181(2): 271-280.e8.
78	Sengupta V, Sengupta S, Lazo A, et al. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19 [J]. Stem Cells Dev, 2020, 29(12): 747-754.
79	Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: present or future [J]. Stem Cell Rev Rep, 2020, 16(3): 427-433.
80	Noone C, Kihm A, English K, et al. IFN-γ stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro [J]. Stem Cells Dev, 2013, 22(22): 3003‐3014.
81	Abumaree MH, Bahattab E, Alsadoun A, et al. Characterization of the interaction between human decidua parietalis mesenchymal stem/stromal cells and natural killer cells [J]. Stem Cell Res Ther, 2018, 9(1): 102.
82	Du Rocher B, Mencalha AL, Gomes BE, et al. Mesenchymal stromal cells impair the differentiation of CD14⁺⁺ CD16^- CD64⁺ classical monocytes into CD14⁺⁺ CD16⁺ CD64⁺⁺ activate monocytes [J]. Cytotherapy, 2012, 14(1): 12‐25.
83	Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population [J]. Blood, 2009, 113(1): 46‐57.
84	Spaggiari GM, Abdelrazik H, Becchetti F, et al. MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2 [J]. Blood, 2009, 113(26): 6576‐6583.
85	Prockop DJ. Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation [J]. Stem Cells, 2013, 31(10): 2042‐2046.
86	Abumaree MH, Al Jumah MA, Kalionis B, et al. Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages [J]. Stem Cell Rev Rep, 2013, 9(5): 620‐641.
87	Giunti D, Parodi B, Usai C, et al. Mesenchymal stem cells shape microglia effector functions through the release of CX3CL1 [J]. Stem Cells, 2012, 30(9): 2044‐2053.
88	Melief SM, Schrama E, Brugman MH, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages [J]. Stem Cells, 2013, 31(9): 1980‐1991.
89	Cassatella MA, Mosna F, Micheletti A, et al. Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils [J]. Stem Cells, 2011, 29(6): 1001-1011.
90	Duffy MM, Ritter T, Ceredig R, et al. Mesenchymal stem cell effects on T-cell effector pathways [J]. Stem Cell Res Ther, 2011, 2(4): 34.
91	Su W, Wan Q, Huang J, et al. Culture medium from TNF-α-stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms [J]. J Allergy Clin Immunol, 2015, 136(2): 423‐432.
92	Wang Y, Chen X, Cao W, et al. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications [J]. Nat Immunol, 2014, 15(11): 1009‐1016.
93	Luz-Crawford P, Djouad F, Toupet K, et al. Mesenchymal stem cell-derived interleukin 1 receptor antagonist promotes macrophage polarization and inhibits B cell differentiation [J]. Stem Cells, 2016, 34(2): 483‐492.
94	Hu J, Zhang X, Zhou LP, et al. Immunomodulatory properties of colonic mesenchymal stem cells [J]. Immunol Lett, 2013, 156(1-2): 23‐29.
95	Sato K, Ozaki K, Oh I, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells [J]. Blood, 2007, 109(1): 228‐234.
96	Prevosto C, Zancolli M, Canevali P, et al. Generation of CD4⁺ or CD8⁺ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction [J]. Haematologica, 2007, 92(7): 881‐888.
97	Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4⁺CD25highFOXP3⁺ regulatory T cells [J]. Stem Cells, 2008, 26(1): 212-222.
98	Khare D, Or R, Resnick I, et al. Mesenchymal Stromal cell-derived exosomes affect mRNA expression and function of B-lymphocytes [J]. Front Immunol, 2018, 9: 3053.
99	Spaggiari GM, Capobianco A, Becchetti S, et al. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation [J]. Blood, 2006, 107(4): 1484‐1490.
100	Chen D, Tang P, Liu L, et al. Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway [J]. Cell Cycle, 2018, 17(7): 858‐867.
101	Asari S, Itakura S, Ferreri K, et al. Mesenchymal stem cells suppress B-cell terminal differentiation [J]. Exp Hematol, 2009, 37(5): 604‐615.

细胞类型		MSCs的调节作用及机制
先天性免疫细胞
	NK	MSCs抑制NK的增殖和功能：（1）通过抑制NK细胞激活的受体（NKp30/44、NKG2D、CD60）的表达抑制其细胞毒作用；（2）通过可溶性因子（PGE2、HLA-G、IDO）抑制NK细胞的增殖和细胞毒作用；（3）IFN-γ诱导MSCs高表达HLA-I类分子，与NK的抑制性受体共同作用，抑制NK细胞毒作用
	DC	MSCs抑制DC的分化、成熟与活性：（1）抑制多能造血干细胞向DC的分化和DC的成熟，降低CD1a、CD80、CD83、CD86、HLA-DR的表达，减少IL-2的分泌；（2）主要通过细胞接触和可溶性因子实现对DC的抑制
	巨噬细胞	MSCs通过多种机制调节巨噬细胞的功能：（1）细胞接触：MSCs通过与巨噬细胞相互作用，上调巨噬细胞中与吞噬功能相关分子的表达，增强其对病原体的吞噬能力；（2）可溶性因子：MSCs通过表达PGE2、IL-6、CX3CL1和IDO直接诱导单核细胞分化为M2型巨噬细胞或诱导M1型转化为M2型巨噬细胞；（3）炎性微环境中时，促炎因子可刺激MSCs分泌TSG-6与巨噬细胞膜上CD44受体相互作用，下调NF-κB信号通路活性，减少促炎因子的表达，削弱促炎级联反应
	中性粒细胞	（1）MSCs通过IL-6依赖的途径减轻其氧爆发，抑制中性粒细胞迁徙；抑制中性粒细胞凋亡，延长寿命；（2）诱导Th2产生IL-17，增强中性粒细胞吞噬功能，使其主要发挥清除病原体的作用
	MCs	MSCs能显著降低IgE的产生、组胺的释放和MCs的活化；MSCs产生TGF-β1，通过降低FcεRI的表达，导致FcεRI介导的MCs脱颗粒作用减弱
适应性免疫细胞
	T细胞	MSCs具有抑制T细胞增殖、抑制T细胞向Th1、Th17分化、促进Tregs的产生的作用：抑制Th1和Th17细胞产生的促炎细胞因子，如TNF-α、IFN-γ和IL-17，增强Th2细胞产生的抗炎细胞因子，如IL-4；抑制CTL的增殖和细胞毒性功能；诱导CD4+T细胞以细胞-细胞接触依赖的方式分化为Tregs （1）细胞接触：ICAM-1是MSCs发挥抑制作用不可或缺的；PD-1/PD-L1相互作用参与了这一过程；（2）可溶性因子：MSCs产生的IDO、PGE、IL-10、TGF-β、NO、HLA-G5、PD-L1、PD-L2和TSG-6等因子与MSCs的免疫抑制功能有关；MSCs以PGE2依赖的方式抑制Th1细胞因子的产生；对于Th17细胞，MSCs通过上调PD-1的表达、IL-10的分泌和PGE2的产生以及CCL2依赖的方式来抑制其分化；PGE2、IL-6、IL-10和TGF-β，参与了CD4+T细胞分化为Tregs的过程；（3）MSCs可抑制T细胞增殖过程，使T细胞被阻滞在G0/G1期
	B细胞	MSCs抑制B细胞的活化、增殖、分化、抗体产生和趋化等一系列活性：（1）MSCs以旁分泌方式阻止B细胞在G0/G1期增殖；（2）细胞-细胞接触依赖性方式，如PD-1与其配体PDL-1的相互作用，介导MSCs对B细胞的抑制；（3）MSCs可以通过下调B淋巴细胞诱导成熟蛋白-1（Blimp-1）的mRNA表达来抑制B细胞向浆细胞的分化

细胞类型		MSCs的调节作用及机制
先天性免疫细胞
	NK	MSCs抑制NK的增殖和功能：（1）通过抑制NK细胞激活的受体（NKp30/44、NKG2D、CD60）的表达抑制其细胞毒作用；（2）通过可溶性因子（PGE2、HLA-G、IDO）抑制NK细胞的增殖和细胞毒作用；（3）IFN-γ诱导MSCs高表达HLA-I类分子，与NK的抑制性受体共同作用，抑制NK细胞毒作用
	DC	MSCs抑制DC的分化、成熟与活性：（1）抑制多能造血干细胞向DC的分化和DC的成熟，降低CD1a、CD80、CD83、CD86、HLA-DR的表达，减少IL-2的分泌；（2）主要通过细胞接触和可溶性因子实现对DC的抑制
	巨噬细胞	MSCs通过多种机制调节巨噬细胞的功能：（1）细胞接触：MSCs通过与巨噬细胞相互作用，上调巨噬细胞中与吞噬功能相关分子的表达，增强其对病原体的吞噬能力；（2）可溶性因子：MSCs通过表达PGE2、IL-6、CX3CL1和IDO直接诱导单核细胞分化为M2型巨噬细胞或诱导M1型转化为M2型巨噬细胞；（3）炎性微环境中时，促炎因子可刺激MSCs分泌TSG-6与巨噬细胞膜上CD44受体相互作用，下调NF-κB信号通路活性，减少促炎因子的表达，削弱促炎级联反应
	中性粒细胞	（1）MSCs通过IL-6依赖的途径减轻其氧爆发，抑制中性粒细胞迁徙；抑制中性粒细胞凋亡，延长寿命；（2）诱导Th2产生IL-17，增强中性粒细胞吞噬功能，使其主要发挥清除病原体的作用
	MCs	MSCs能显著降低IgE的产生、组胺的释放和MCs的活化；MSCs产生TGF-β1，通过降低FcεRI的表达，导致FcεRI介导的MCs脱颗粒作用减弱
适应性免疫细胞
	T细胞	MSCs具有抑制T细胞增殖、抑制T细胞向Th1、Th17分化、促进Tregs的产生的作用：抑制Th1和Th17细胞产生的促炎细胞因子，如TNF-α、IFN-γ和IL-17，增强Th2细胞产生的抗炎细胞因子，如IL-4；抑制CTL的增殖和细胞毒性功能；诱导CD4+T细胞以细胞-细胞接触依赖的方式分化为Tregs （1）细胞接触：ICAM-1是MSCs发挥抑制作用不可或缺的；PD-1/PD-L1相互作用参与了这一过程；（2）可溶性因子：MSCs产生的IDO、PGE、IL-10、TGF-β、NO、HLA-G5、PD-L1、PD-L2和TSG-6等因子与MSCs的免疫抑制功能有关；MSCs以PGE2依赖的方式抑制Th1细胞因子的产生；对于Th17细胞，MSCs通过上调PD-1的表达、IL-10的分泌和PGE2的产生以及CCL2依赖的方式来抑制其分化；PGE2、IL-6、IL-10和TGF-β，参与了CD4+T细胞分化为Tregs的过程；（3）MSCs可抑制T细胞增殖过程，使T细胞被阻滞在G0/G1期
	B细胞	MSCs抑制B细胞的活化、增殖、分化、抗体产生和趋化等一系列活性：（1）MSCs以旁分泌方式阻止B细胞在G0/G1期增殖；（2）细胞-细胞接触依赖性方式，如PD-1与其配体PDL-1的相互作用，介导MSCs对B细胞的抑制；（3）MSCs可以通过下调B淋巴细胞诱导成熟蛋白-1（Blimp-1）的mRNA表达来抑制B细胞向浆细胞的分化

注册号	题目	试验开始时间	患者数量	实验持续时间	研究类型
NCT4348461	Battle against COVID-19 using mesenchymal stromal cells	2020/4/6	100	5个月	干预性研究
NCT4315987	Mesenchymal stem cell to treat patients with severe COVID-19 pneumonia	2020/3/20	66	3个月	干预性研究
NCT4352803	Adipose mesenchymal cells for abatement of SARS-CoV-2 respiratory compromise in COVID-19 disease	2020/4/20	20	6年	干预性研究
NCT4252118	Mesenchymal stem cell treatment for pneumonia patients infected with COVID-19	2020/1/27	20	1年	干预性研究
NCT4345601	Mesenchymal stromal cells for the treatment of SARS-CoV-2 induced acute respiratory failure （COVID-19 disease）	2020/4/14	30	2年	干预性研究
NCT4313322	Treatment of COVID-19 patients using Whartons Jelly-mesenchymal stem cells	2020/3/16	5	6个月	干预性研究
NCT4288102	Treatment with mesenchymal stem cells for severe corona virus disease 2019	2020/4/5	90	4个月	干预性研究
NCT4346368	Bone marrow-derived mesenchymal stem cell treatment for sebere patients with corona virus disease 2019 （COVID-19）	2020/4/15	20	8个月	干预性研究
NCT4336254	Safety and efficacy study of allogenic human dental pulp mesenchymal stem cells to treat severe COVID-19 patients	2020/4/6	20	8个月	干预性研究
NCT4273646	Study of human umbilical cord mesenchymal stem cells in the treatment of severe COVID-19	2020/4/20	48	5个月	干预性研究
NCT4302519	Novel coronavirus induced severe pneumonia treated by dental pulp mesenchymal stem cells	2020/4/5	24	4个月	干预性研究
NCT4339660	Clinical Research of Human Mesenchymal Stem Cells in the Treatment of COVID-19 Pneumonia	2020/2/1	30	4个月	干预性研究
NCT4355728	Use of UC-MSCs for COVID-19 Patients	2020/4/17	24	1 年	干预性研究
NCT4362189	Efficacy and Safety Study of Allogeneic HB-adMSCs for the Treatment of COVID-19	2020/5/15	110	5个月	干预性研究
NCT4361942	Treatment of Severe COVID-19 Pneumonia With Allogeneic Mesenchymal Stromal Cells （COVID_MSV）（COVID_MSV）	2020/4/24	24	8个月	干预性研究
NCT3042143	Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration （REALIST）（COVID-19）（REALIST）	2019/1/7	75	3年	干预性研究
NCT4269525	Umbilical Cord （UC）-Derived Mesenchymal Stem Cells （MSCs） Treatment for the 2019-novel Coronavirus（nCOV） Pneumonia	2020/2/6	10	7个月	干预性研究
NCT4333368	Cell Therapy Using Umbilical Cord-derived Mesenchymal Stromal Cells in SARS-CoV-2-related ARDS （STROMA-CoV2）	2020/4/1	60	1年	干预性研究
NCT4341610	ASC Therapy for Patients With Severe Respiratory COVID-19 （ASC COVID-19）	2020/4/20	40	1年	干预性研究
NCT4366323	Clinical Trial to Assess the Safety and Efficacy of Intravenous Administration of Allogeneic Adult Mesenchymal Stem Cells of Expanded Adipose Tissue in Patients With Severe Pneumonia Due to COVID-19	2020/4/28	26	18个月	干预性研究
NCT4371601	Safety and Effectiveness of Mesenchymal Stem Cells in the Treatment of Pneumonia of Coronavirus Disease 2019	2020/5/1	60	18个月	干预性研究
NCT4366063	Mesenchymal Stem Cell Therapy for SARS-CoV-2-related Acute Respiratory Distress Syndrome	2020/4/28	60	6个月	干预性研究
NCT4382547	Treatment of Covid-19 Associated Pneumonia With Allogenic Pooled Olfactory Mucosa-derived Mesenchymal Stem Cells	2020/4/21	24	1年	干预性研究
NCT4366271	Clinical Trial of Allogeneic Mesenchymal Cells From Umbilical Cord Tissue in Patients With COVID-19	2020/4/28	106	1年	干预性研究
NCT4390152	Safety and Efficacy of Intravenous Wharton's Jelly Derived Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome Due to COVID 19	2020/5/15	40	1年	干预性研究
NCT4377334	Mesenchymal Stem Cells （MSCs） in Inflammation-Resolution Programs of Coronavirus Disease 2019 （COVID-19） Induced Acute Respiratory Distress Syndrome （ARDS）	2020/5/6	40	9个月	干预性研究
NCT4390139	Efficacy and Safety Evaluation of Mesenchymal Stem Cells for the Treatment of Patients With Respiratory Distress Due to COVID-19	2020/5/15	30	7个月	干预性研究
NCT4392778	Clinical Use of Stem Cells for the Treatment of Covid-19	2020/4/1	30	5个月	干预性研究
NCT4397796	Study of the Safety of Therapeutic Tx With Immunomodulatory MSC in Adults With COVID-19 Infection Requiring Mechanical Ventilation	2020/5/21	45	1年	干预性研究
NCT4371393	MSCs in COVID-19 ARDS	2020/5/1	300	2年	干预性研究
NCT4398303	ACT-20 in Patients With Severe COVID-19 Pneumonia	2020/5/21	70	5个月	干预性研究
NCT4400032	Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome - Vanguard	2020/5/25	9	1年	干预性研究
NCT4276987	A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia	2020/2/15	30	5个月	干预性研究
ChiCTR2000031430	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	2020/3/31	100	21个月	干预性研究
ChiCTR2000030944	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	2020/3/18	10	5个月	干预性研究
ChiCTR2000030866	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	2020/03/16	30	10个月	观察性研究
ChiCTR2000030835	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	2020/03/15	10	1年	干预性研究
ChiCTR2000030484	脐带间充质干细胞联合细胞外泌体静脉输注对新型冠状病毒肺炎（COVID-19）肺损伤修复的临床应用研究	2020/03/03	30	1年	干预性研究
ChiCTR2000030138	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（该研究目前尚未获得伦理委员会批准）	2020/02/24	30	3个月	干预性研究

注册号	题目	试验开始时间	患者数量	实验持续时间	研究类型
NCT4348461	Battle against COVID-19 using mesenchymal stromal cells	2020/4/6	100	5个月	干预性研究
NCT4315987	Mesenchymal stem cell to treat patients with severe COVID-19 pneumonia	2020/3/20	66	3个月	干预性研究
NCT4352803	Adipose mesenchymal cells for abatement of SARS-CoV-2 respiratory compromise in COVID-19 disease	2020/4/20	20	6年	干预性研究
NCT4252118	Mesenchymal stem cell treatment for pneumonia patients infected with COVID-19	2020/1/27	20	1年	干预性研究
NCT4345601	Mesenchymal stromal cells for the treatment of SARS-CoV-2 induced acute respiratory failure （COVID-19 disease）	2020/4/14	30	2年	干预性研究
NCT4313322	Treatment of COVID-19 patients using Whartons Jelly-mesenchymal stem cells	2020/3/16	5	6个月	干预性研究
NCT4288102	Treatment with mesenchymal stem cells for severe corona virus disease 2019	2020/4/5	90	4个月	干预性研究
NCT4346368	Bone marrow-derived mesenchymal stem cell treatment for sebere patients with corona virus disease 2019 （COVID-19）	2020/4/15	20	8个月	干预性研究
NCT4336254	Safety and efficacy study of allogenic human dental pulp mesenchymal stem cells to treat severe COVID-19 patients	2020/4/6	20	8个月	干预性研究
NCT4273646	Study of human umbilical cord mesenchymal stem cells in the treatment of severe COVID-19	2020/4/20	48	5个月	干预性研究
NCT4302519	Novel coronavirus induced severe pneumonia treated by dental pulp mesenchymal stem cells	2020/4/5	24	4个月	干预性研究
NCT4339660	Clinical Research of Human Mesenchymal Stem Cells in the Treatment of COVID-19 Pneumonia	2020/2/1	30	4个月	干预性研究
NCT4355728	Use of UC-MSCs for COVID-19 Patients	2020/4/17	24	1 年	干预性研究
NCT4362189	Efficacy and Safety Study of Allogeneic HB-adMSCs for the Treatment of COVID-19	2020/5/15	110	5个月	干预性研究
NCT4361942	Treatment of Severe COVID-19 Pneumonia With Allogeneic Mesenchymal Stromal Cells （COVID_MSV）（COVID_MSV）	2020/4/24	24	8个月	干预性研究
NCT3042143	Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration （REALIST）（COVID-19）（REALIST）	2019/1/7	75	3年	干预性研究
NCT4269525	Umbilical Cord （UC）-Derived Mesenchymal Stem Cells （MSCs） Treatment for the 2019-novel Coronavirus（nCOV） Pneumonia	2020/2/6	10	7个月	干预性研究
NCT4333368	Cell Therapy Using Umbilical Cord-derived Mesenchymal Stromal Cells in SARS-CoV-2-related ARDS （STROMA-CoV2）	2020/4/1	60	1年	干预性研究
NCT4341610	ASC Therapy for Patients With Severe Respiratory COVID-19 （ASC COVID-19）	2020/4/20	40	1年	干预性研究
NCT4366323	Clinical Trial to Assess the Safety and Efficacy of Intravenous Administration of Allogeneic Adult Mesenchymal Stem Cells of Expanded Adipose Tissue in Patients With Severe Pneumonia Due to COVID-19	2020/4/28	26	18个月	干预性研究
NCT4371601	Safety and Effectiveness of Mesenchymal Stem Cells in the Treatment of Pneumonia of Coronavirus Disease 2019	2020/5/1	60	18个月	干预性研究
NCT4366063	Mesenchymal Stem Cell Therapy for SARS-CoV-2-related Acute Respiratory Distress Syndrome	2020/4/28	60	6个月	干预性研究
NCT4382547	Treatment of Covid-19 Associated Pneumonia With Allogenic Pooled Olfactory Mucosa-derived Mesenchymal Stem Cells	2020/4/21	24	1年	干预性研究
NCT4366271	Clinical Trial of Allogeneic Mesenchymal Cells From Umbilical Cord Tissue in Patients With COVID-19	2020/4/28	106	1年	干预性研究
NCT4390152	Safety and Efficacy of Intravenous Wharton's Jelly Derived Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome Due to COVID 19	2020/5/15	40	1年	干预性研究
NCT4377334	Mesenchymal Stem Cells （MSCs） in Inflammation-Resolution Programs of Coronavirus Disease 2019 （COVID-19） Induced Acute Respiratory Distress Syndrome （ARDS）	2020/5/6	40	9个月	干预性研究
NCT4390139	Efficacy and Safety Evaluation of Mesenchymal Stem Cells for the Treatment of Patients With Respiratory Distress Due to COVID-19	2020/5/15	30	7个月	干预性研究
NCT4392778	Clinical Use of Stem Cells for the Treatment of Covid-19	2020/4/1	30	5个月	干预性研究
NCT4397796	Study of the Safety of Therapeutic Tx With Immunomodulatory MSC in Adults With COVID-19 Infection Requiring Mechanical Ventilation	2020/5/21	45	1年	干预性研究
NCT4371393	MSCs in COVID-19 ARDS	2020/5/1	300	2年	干预性研究
NCT4398303	ACT-20 in Patients With Severe COVID-19 Pneumonia	2020/5/21	70	5个月	干预性研究
NCT4400032	Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome - Vanguard	2020/5/25	9	1年	干预性研究
NCT4276987	A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia	2020/2/15	30	5个月	干预性研究
ChiCTR2000031430	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	2020/3/31	100	21个月	干预性研究
ChiCTR2000030944	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	2020/3/18	10	5个月	干预性研究
ChiCTR2000030866	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	2020/03/16	30	10个月	观察性研究
ChiCTR2000030835	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	2020/03/15	10	1年	干预性研究
ChiCTR2000030484	脐带间充质干细胞联合细胞外泌体静脉输注对新型冠状病毒肺炎（COVID-19）肺损伤修复的临床应用研究	2020/03/03	30	1年	干预性研究
ChiCTR2000030138	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（该研究目前尚未获得伦理委员会批准）	2020/02/24	30	3个月	干预性研究

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[2]	Zhuoyi Fu, Shengcheng Tang, Qiaomei Bu, Gaobing Xu, Anping Wu, Wei Cai, Ming Yang, Haitao Tan. Research progress of magnesium in treatment of osteoarthritis [J]. Chinese Journal of Joint Surgery(Electronic Edition), 2023, 17(03): 354-362.
[3]	Tingting Li, Heyu Wu, Yue Zhang, Kang Cheng, Xiaofang Zhang, Yachan Cheng. Study on the application of combined insulation strategy in laparoscopic anatomic hepatectomy in elderly patients [J]. Chinese Journal of Operative Procedures of General Surgery(Electronic Edition), 2023, 17(05): 522-525.
[4]	Yingjun Tang, Huajuan Li, Saini Wang, Wang Xu, Feng Liu, Xi Li, Xinbao Hao, Huaping Huang. Effect and mechanism of human umbilical cord mesenchymal stem cells (HU-MSCs) transplantation on emphysema mice [J]. Chinese Journal of Lung Diseases(Electronic Edition), 2023, 16(04): 476-480.
[5]	Ye Li, Jie He, Jinxiu Hu, Jinxiang Wang, Chuan Tian, Hang Pan, Mengdie Chen, Xiaojuan Zhao, Li Ye, Min Zhang, Xinghua Pan. Highly active mesenchymal stem cells interfere with ovarian aging in macaques [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 210-219.
[6]	Huiling Long, Mi Lin, Ting Shao. Research progress and application of three-dimensional spherical mesenchymal stem cell culture technology [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 229-234.
[7]	Wenhui Liu, Tao Wu, Xi Zhang. Advances in mesenchymal stem cells combined with thrombopoietin receptor agonists in platelet recovery after allogeneic hematopoietic stem cell transplantation [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(04): 242-246.
[8]	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.
[9]	Fuhao Qin, Zheng Zheng, Bin Jiang. Research progress of mesenchymal stem cells in the treatment of perianal fifistulizing Crohn's disease [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(03): 172-177.
[10]	Jiuli Yuan, Dan Liu, Linli Li, Jinyu Liu. Basic research and clinical application of hair follicle-derived mesenchymal stem cells [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(03): 189-192.
[11]	Xing Feng, Hongtao Jin, Jun Ma, Yongzhou Song, Aijing Liu. Progress in the treatment of inflammatory arthritis with mesenchymal stem cells [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(02): 87-92.
[12]	Shuangyin Lei, Jianxin Xi, Yuxuan He, Jingyi Yao, Boya Shi, Jie Ma, Guangfan Chi, Meiying Li. Applications and advances of mesenchymal stem cells-derived exosomes in treating neurodegenerative diseases [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(02): 93-100.
[13]	Hechun Tang, Shanping Ye, Dongning Liu, Weiquan Zhu, Zhixiang Huang, Taiyuan Li. A prospective randomized controlled study of the effect of natural orifice specimen extraction during robotic rectal radical resection on stress response and cellular immune function [J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2023, 12(04): 272-281.
[14]	Yunzhao Yang, Cheng Zhou, Meihan Shi, Jing Zhao, Xueyuan Bai. Therapeutic effect of human amniotic fluid-derived mesenchymal stem cells on membranous nephropathy in rats [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2023, 12(04): 181-186.
[15]	Yanqi Song, Xuejing Ren, Wenjuan Wang, Qiuxia Han, Yue Xu, Kaiting Zhuang, Tuo Xiao, Guangyan Cai. Effect of mesenchymal stem cells on ferroptosis in cisplatin-induced acute kidney injury of mice [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2023, 12(04): 187-193.

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