Effects of allogeneic bone marrow mesenchymal stem cells infusion on the expression of CXCL12/CXCR4 in the kidney of MRL/lpr lupus mice

doi:10.12307/2022.380

Abstract

Abstract: BACKGROUND: Chemokine CXCL12 and its receptor CXCR4 play a certain role in the pathogenesis of lupus nephritis, and it is of significance to explore the effect of bone marrow mesenchymal stem cells infusion on the expression of CXCL12/CXCR4 in lupus kidney for further study of the pathogenesis of lupus nephritis and the mechanism of bone marrow mesenchymal stem cells in the treatment of lupus nephritis.
OBJECTIVE: To investigate the effect of allogeneic bone marrow mesenchymal stem cell infusion on the expression of CXCL12/CXCR4 in the kidney of MRL/lpr lupus mice.
METHODS: Bone marrow mesenchymal stem cells of C57BL/6 mice were isolated and cultured, expanded to the third passage, and the cell concentration was 1×109 L-1. Totally 15 female MRL/lpr mice aged four to five weeks were selected and divided into MRL/lpr group (no tail vein infusion), PBS group (PBS injection at the end of 12 weeks), and bone marrow mesenchymal stem cell group (injection of bone marrow mesenchymal stem cells at the end of 12 weeks) (n=5 per group). An additional five C57BL/6 mice were selected as normal controls. Mice in each group were sacrificed at the end of 20 weeks of age. The expression of CXCL12 in peripheral blood plasma was detected by ELISA. The expression of CXCR4 on B lymphocyte surface in peripheral blood and kidney was analyzed by flow cytometry. The expression of CXCL12 in the kidney was demonstrated by immunohistochemistry. The pathological changes of the kidney tissue were observed by hematoxylin-eosin staining.
RESULTS AND CONCLUSION: (1) Compared with the C57BL/6 group, the expression of CXCL12 in peripheral blood plasma and kidney was increased, and the expression of CXCR4 on B lymphocyte surface in peripheral blood and kidney was also increased in the MRL/lpr group. (2) Compared with PBS group, the expression levels of CXCL12 in peripheral blood plasma and kidney of lupus mice were decreased, and CXCR4 expression levels on the surface of B lymphocytes in peripheral blood and kidney of lupus mice were similarly decreased in the bone marrow mesenchymal stem cell group. (3) Hematoxylin-eosin staining suggested that kidney injury was relieved in lupus mice after infusion of bone marrow mesenchymal stem cells. (4) It is concluded that there is abnormal expression of CXCL12/CXCR4 in the kidney of MRL/lpr lupus mice, and bone marrow mesenchymal stem cell infusion may play a therapeutic role by affecting the expression of CXCL12/CXCR4.

Key words: stem cells, bone marrow mesenchymal stem cells, lupus nephritis, systemic lupus erythematosus, chemokine, CXCL12, CXCR4

CLC Number:

Cheng Mengwei, Tang Yu, Ma Cui, Shi Wei, Zheng Wenjuan, Qiu Yingying, Rui Jinbing, Wang Yanru. Effects of allogeneic bone marrow mesenchymal stem cells infusion on the expression of CXCL12/CXCR4 in the kidney of MRL/lpr lupus mice[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(19): 3018-3023.

Figures/Tables 4

References

[1] SONG K, LIU L, ZHANG X, et al. An update on genetic susceptibility in lupus nephritis. Clin Immunol. 2020;210:108272.
[2] GAO L, BIRD AK, MEEDNU N, et al. Bone Marrow-Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence-Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein-Interferon-β Feedback Loop. Arthritis Rheumatol. 2017;69(8):1623-1635.
[3] 史伟,史敦绘,王丽霞,等. BMMSCs输注对MRL/lpr狼疮鼠血液系统的影响[J].南京医科大学学报(自然科学版),2019,39(4):485-490.
[4] SUN L, AKIYAMA K, ZHANG H, et al. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells. 2009;27(6):1421-1432.
[5] SCHENA F, GAMBINI C, GREGORIO A, et al. Interferon-γ-dependent inhibition of B cell activation by bone marrow-derived mesenchymal stem cells in a murine model of systemic lupus erythematosus. Arthritis Rheum. 2010;62(9):2776-2786.
[6] ZHOU T, LIAO C, LI HY, et al. Efficacy of mesenchymal stem cells in animal models of lupus nephritis: a meta-analysis. Stem Cell Res Ther. 2020;11(1):48.
[7] LIANG J, ZHANG H, KONG W, et al. Safety analysis in patients with autoimmune disease receiving allogeneic mesenchymal stem cells infusion: a long-term retrospective study. Stem Cell Res Ther. 2018; 9(1):312.
[8] BARBADO J, TABERA S, SÁNCHEZ A, et al. Therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis. Lupus. 2018;27(13):2161-2165.
[9] WANG D, ZHANG H, LIANG J, et al. Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transplant. 2013;22(12):2267-2277.
[10] WANG D, ZHANG H, LIANG J, et al. A Long-Term Follow-Up Study of Allogeneic Mesenchymal Stem/Stromal Cell Transplantation in Patients with Drug-Resistant Systemic Lupus Erythematosus. Stem Cell Reports. 2018;10(3):933-941.
[11] YANG X, YANG J, LI X, et al. Bone marrow-derived mesenchymal stem cells inhibit T follicular helper cell in lupus-prone mice. Lupus. 2018;27(1):49-59.
[12] DELAROSA O, LOMBARDO E, BERAZA A, et al. Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng Part A. 2009;15(10):2795-2806.
[13] FU X, LIU G, HALIM A, et al. Mesenchymal Stem Cell Migration and Tissue Repair. Cells. 2019;8(8):784.
[14] 束庆,范晴晴,刘蕴星,等.间充质干细胞移植在治疗自身免疫性疾病中的应用进展[J].药学进展,2019,43(4):276-281.
[15] SHACHAR I, KARIN N. The dual roles of inflammatory cytokines and chemokines in the regulation of autoimmune diseases and their clinical implications. J Leukoc Biol. 2013;93(1):51-61.
[16] MOUSAVI A. CXCL12/CXCR4 signal transduction in diseases and its molecular approaches in targeted-therapy. Immunol Lett. 2020;217: 91-115.
[17] LIAO X, PIRAPAKARAN T, LUO XM. Chemokines and Chemokine Receptors in the Development of Lupus Nephritis. Mediators Inflamm. 2016;2016:6012715.
[18] ARAZI A, RAO DA, BERTHIER CC, et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol. 2019;20(7):902-914.
[19] CHENG Q, KHODADADI L, TADDEO A, et al. CXCR4-CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice. Eur J Immunol. 2018;48(6):1020-1029.
[20] ALMAANI S, MEARA A, ROVIN BH. Update on Lupus Nephritis. Clin J Am Soc Nephrol. 2017;12(5):825-835.
[21] DEVARAPU SK, KUMAR VR S, RUPANAGUDI KV, et al. Dual blockade of the pro-inflammatory chemokine CCL2 and the homeostatic chemokine CXCL12 is as effective as high dose cyclophosphamide in murine proliferative lupus nephritis. Clin Immunol. 2016;169:139-147.
[22] SATTWIKA PD, MUSTAFA R, PARAMAISWARI A, et al. Stem cells for lupus nephritis: a concise review of current knowledge. Lupus. 2018; 27(12):1881-1897.
[23] ZHAO W, WU C, LI LJ, et al. RNAi Silencing of HIF-1α Ameliorates Lupus Development in MRL/lpr Mice. Inflammation. 2018;41(5):1717-1730.
[24] GU Z, TAN W, JI J, et al. Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway. Aging (Albany NY). 2016;8(5):1102-1114.
[25] 王丽霞,陆化,费小明,等. MRL/lpr狼疮鼠骨髓间充质干细胞表面粘附分子N-钙粘附蛋白表达增高并伴有骨髓中B淋巴细胞生成障碍[J].中国实验血液学杂志,2019,27(3):964-969.
[26] 宋冬明,崔婷,裘影影,等.肿瘤坏死因子-α抑制狼疮鼠(MRL/lpr)骨髓间充质干细胞成骨分化参与骨质疏松机制的体内研究[J].中华风湿病学杂志,2015,19(6):364-368.
[27] WANG A, FAIRHURST AM, TUS K, et al. CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus. J Immunol. 2009; 182(7):4448-4458.
[28] LIU J, LU X, LOU Y, et al. Xenogeneic Transplantation of Human Placenta-Derived Mesenchymal Stem Cells Alleviates Renal Injury and Reduces Inflammation in a Mouse Model of Lupus Nephritis. Biomed Res Int. 2019;2019:9370919.
[29] YU Y, WU RX, GAO LN, et al. Stromal cell-derived factor-1-directed bone marrow mesenchymal stem cell migration in response to inflammatory and/or hypoxic stimuli. Cell Adh Migr. 2016;10(4):342-359.
[30] CHOI EW, LEE HW, SHIN IS, et al. Comparative Efficacies of Long-Term Serial Transplantation of Syngeneic, Allogeneic, Xenogeneic, or CTLA4Ig-Overproducing Xenogeneic Adipose Tissue-Derived Mesenchymal Stem Cells on Murine Systemic Lupus Erythematosus. Cell Transplant. 2016;25(6):1193-1206.
[31] PARK MJ, KWOK SK, LEE SH, et al. Adipose tissue-derived mesenchymal stem cells induce expansion of interleukin-10-producing regulatory B cells and ameliorate autoimmunity in a murine model of systemic lupus erythematosus. Cell Transplant. 2015;24(11):2367-2377.
[32] DANG J, XU Z, XU A, et al. Human gingiva-derived mesenchymal stem cells are therapeutic in lupus nephritis through targeting of CD39-CD73 signaling pathway. J Autoimmun. 2020;113:102491.
[33] WANG D, HUANG S, YUAN X, et al. The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus. Cell Mol Immunol. 2017;14(5):423-431.
[34] 巩小凡,贺颖,方明红,等.间充质干细胞治疗系统性红斑狼疮的研究进展[J].吉林医药学院学报,2020,41(5):363-365.
[35] FUNARI A, ALIMANDI M, PIERELLI L, et al. Human Sinusoidal Subendothelial Cells Regulate Homing and Invasion of Circulating Metastatic Prostate Cancer Cells to Bone Marrow. Cancers (Basel). 2019;11(6):763.
[36] OH EJ, LEE HW, KALIMUTHU S, et al. In vivo migration of mesenchymal stem cells to burn injury sites and their therapeutic effects in a living mouse model. J Control Release. 2018;279:79-88.
[37] HEMATTI P, KIM J, STEIN AP, et al. Potential role of mesenchymal stromal cells in pancreatic islet transplantation. Transplant Rev (Orlando). 2013;27(1):21-29.
[38] DE MIGUEL MP, FUENTES-JULIÁN S, BLÁZQUEZ-MARTÍNEZ A, et al. Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med. 2012;12(5):574-591.
[39] 罗利梅,骆辑,周晓泉,等.间充质干细胞对系统性红斑狼疮T淋巴细胞的免疫调节作用[J].免疫学杂志,2016,32(8):681-686.
[40] 陈海凤,邹耀红,孙凌云.瘦素对骨髓间充质干细胞及免疫细胞亚群的调控作用及其对狼疮鼠病情的影响[J].中华风湿病学杂志, 2018,22(8):516-521.