间充质干细胞在肾脏疾病治疗中的应用进展

doi:10.16352/j.issn.1001-6325.2023.01.0030

摘要/Abstract

摘要： 间充质干细胞可以通过旁分泌各种细胞因子减轻炎性反应和恢复肾脏损伤,以及通过调控免疫细胞维持免疫稳态。临床前研究表明,间充质干细胞对急性肾损伤、糖尿病肾病、狼疮性肾炎及各种肾小球疾病动物模型均有明显的治疗效果。临床研究中也证明了间充质干细胞治疗人类肾病是安全、有效的。间充质干细胞疗法揭开了肾脏疾病领域新的生物治疗模式。

关键词: 间充质干细胞, 肾脏疾病, 免疫反应

Abstract: Mesenchymal stem cells (MSCs) can reduce inflammation, restore renal injury and maintain immune homeostasis by paracrine various cytokines and regulating immune cells. In preclinical studies, it has been proved that mesenchymal stem cells have obvious therapeutic effects on acute kidney injury, diabetic nephropathy, lupus nephritis and various glomerular diseases in animal models. In clinical studies, mesenchymal stem cells have also been shown to be safe and partially effective. Mesenchymal stem cell therapy has revealed a new model of biotherapy in kidney diseases.

Key words: mesenchymal stem cells, nephropathy, immune response

中图分类号:

R692

杨蕴钊, 石美涵, 周诚, 白雪源. 间充质干细胞在肾脏疾病治疗中的应用进展[J]. 基础医学与临床, 2023, 43(1): 30-37.

YANG Yunzhao, SHI Meihan, ZHOU Cheng, BAI Xueyuan. Progress in application of mesenchymal stem cells in treatment of nephropathy[J]. Basic & Clinical Medicine, 2023, 43(1): 30-37.

参考文献

[1] Ryu JS, Jeong EJ, Kim JY, et al. Application of mesenchymal stem cells in inflammatory and fibrotic diseases[J]. Int J Mol Sci, 2020, 21: 8366.
[2] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors[J]. Cell, 2006, 126: 663-676.
[3] Miceli V, Bulati M, Iannolo G, et al. Therapeutic properties of mesenchymal stromal/stem cells: the need of cell priming for cell-free therapies in regenerative medicine[J]. Int J Mol Sci, 2021, 22: 763.
[4] Strem BM, Hicok KC, Zhu M, et al. Multipotential differentiation of adipose tissue-derived stem cells[J]. Keio J Med, 2005, 54: 132-141.
[5] Li X, Bai J, Ji X, et al. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation[J]. Int J Mol Med, 2014, 34: 695-704.
[6] Chang C, Yan J, Yao Z, et al. Effects of mesenchymal stem cell-derived paracrine signals and their delivery strategies[J]. Adv Healthc Mater, 2021, 10: e2001689.
[7] Harrell CR,Jankovic MG,Fellabaum C, et al. Molecular mechanisms responsible for anti-inflammatory and immunosuppressive effects of mesenchymal stem cell-derived factors[J]. Adv Exp Med Biol, 2019, 1084: 187-206.
[8] Birtwistle L, Chen XM, Pollock C. Mesenchymal stem cell-derived extracellular vesicles to the rescue of renal injury[J]. Int J Mol Sci, 2021, 22: 6596.
[9] Nikolic A, John D, Jean F, et al. Intraperitoneal administration of mesenchymal stem cells ameliorates acute dextran sulfate sodium-induced colitis by suppressing den-dritic cells[J]. Biomed Pharmacother, 2018, 100: 426-432.
[10] Moloudizargari M, Govahi A, Fallah M, et al. The mechanisms of cellular crosstalk between mesenchymal stem cells and natural killer cells: Therapeutic implications[J]. J Cell Physiol, 2021, 236: 2413-2429.
[11] Shi Y, Wang Y, Li Q, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases[J]. Nat Rev Nephrol, 2018, 14: 493-507.
[12] Savio-Silva C, Soinski-Sousa PE, Balby-Rocha M, et al. Mesenchymal stem cell therapy in acute kidney injury (AKI): review and perspectives[J]. Rev Assoc Med Bras (1992), 2020, 66 Suppl 1: s45-s54.
[13] Selim RE, Ahmed HH, Abd-Allah SH, et al. Mesenchy-mal stem cells: a promising therapeutic tool for acute kidney injury[J]. App Biochem Biotechnol, 2019, 189: 284-304.
[14] Tang M, Zhang K, Li Y, et al. Mesenchymal stem cells alleviate acute kidney injury by down-regulating C5a/C5aR pathway activation[J]. Int Urol Nephrol, 2018, 50: 1545-1553.
[15] Zhao L, Hu C, Zhang P, et al. Mesenchymal stem cell therapy targeting mitochondrial dysfunction in acute kidney injury[J]. J Transl Med, 2019, 17: 142.
[16] Anna G, John D, Jean F. et al. Initial report on a phase I clinical trial: Prevention and treatment of post-operative acute kidney injury with allogeneic Mesenchymal stem cells in patients who require on-pump cardiac surgery[J]. Cell Ther Transplant, 2008, 1: 31-35
[17] Swaminathan M, Stafford-Smith M, Chertow GM, et al. Allogeneic mesenchymal stem cells for treatment of AKI after cardiac surgery[J]. J Am Soc Nephrol, 2018, 29: 260-267.
[18] Swaminathan M, Kopyt N, Atta MG, et al. Pharmacological effects of ex vivo mesenchymal stem cell immuno-therapy in patients with acute kidney injury and underlying systemic inflammation[J]. Stem Cells Transl Med, 2021, 10: 1588-1601.
[19] Yang Y, Gao J, Wang S, et al. Efficacy of umbilical cord mesenchymal stem cell transfusion for the treatment of severe AKI: a protocol for a randomised controlled trial[J]. BMJ Open, 2022, 12: e47622.
[20] Calle P, Hotter G. Macrophage phenotype and fibrosis in diabetic nephropathy[J]. Int J Mol Sci, 2020, 21:2806.
[21] Yuan Y, Li L, Zhu L, et al. Mesenchymal stem cells elicit macrophages into M2 phenotype via improving transcription factor EB-mediated autophagy to alleviate diabetic nephropathy[J]. Stem Cells, 2020, 38: 639-652.
[22] Li Y, Liu J, Liao G, et al. Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment[J]. Int J Mol Med, 2018, 41: 2629-2639.
[23] Zhang F, Wang C, Wen X, et al. Mesenchymal stem cells alleviate rat diabetic nephropathy by suppressing CD103(+) DCs-mediated CD8(+) T cell responses[J]. J Cell Mol Med, 2020, 24: 5817-5831.
[24] Sávio-Silva C, Soinski-Sousa PE, Simplício-Filho A, et al. Therapeutic potential of mesenchymal stem cells in a pre-clinical model of diabetic kidney disease and obesity[J]. Int J Mol Sci, 2021, 22: 1546.
[25] Lin W, Li H Y, Yang Q, et al. Administration of mesenchymal stem cells in diabetic kidney disease: a systematic review and meta-analysis[J]. Stem Cell Res Ther, 2021, 12: 43.
[26] Packham DK, Fraser IR, Kerr PG, et al. Allogeneic mesenchymal precursor cells (MPC) in diabetic nephropathy: A Randomized, Placebo-controlled, Dose Escala-tion Study[J]. eBioMedicine, 2016, 12: 263-269.
[27] Almaani S, Meara A, Rovin BH. Update on lupus nephritis[J]. Clin J Am Soc Nephrol, 2017, 12: 825-835.
[28] Zhou T, Liao C, Li H, et al. Efficacy of mesenchymal stem cells in animal models of lupus nephritis: a meta-analysis[J]. Stem Cell Res Ther, 2020, 11: 48.
[29] 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: 1421-1432.
[30] Zhang Z, Niu L, Tang X, et al. Mesenchymal stem cells prevent podocyte injury in lupus-prone B6.MRL-Faslpr mice via polarizing macrophage into an anti-inflammatory phenotype[J]. Nephrol Dial Transplant, 2019, 34: 597-605.
[31] Ma X, Che N, Gu Z, et al. Allogenic mesenchymal stem cell transplantation ameliorates nephritis in lupus mice via inhibition of B-cell activation[J]. Cell Transplant, 2013, 22: 2279-2290.
[32] Li J, Luo M, Li B, et al. Immunomodulatory activity of mesenchymal stem cells in lupus nephritis: advances and applications[J]. Front Immunol, 2022, 13: 843192.
[33] Gu F, Wang D, Zhang H, et al. Allogeneic mesenchy-mal stem cell transplantation for lupus nephritis patients refractory to conventional therapy[J]. Clin Rheumatol, 2014, 33: 1611-1619.
[34] Martínez HR, Molina-Lopez JF, González-Garza MT, et al. Stem cell transplantation in amyotrophic lateral sclerosis patients: methodological approach, safety, and feasibility[J]. Cell Transplant, 2012, 21: 1899-1907.
[35] Wang D, Li J, Zhang Y, et al. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study[J]. Arthritis Res Ther, 2014, 16: R79.
[36] 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 Rheumatic Dis, 2017, 76: 1436-1439.
[37] Suzuki T, Iyoda M, Shibata T, et al. Therapeutic effects of human mesenchymal stem cells in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulone-phritis[J]. PLoS One, 2013, 8: e67475.
[38] Iseri K, Iyoda M, Ohtaki H, et al. Therapeutic effects and mechanism of conditioned media from human mesenchymal stem cells on anti-GBM glomerulonephritis in WKY rats[J]. Am J Physiol-Renal Physiol, 2016, 310: F1182-F1191.
[39] Li Y, Raman I, Du Y, et al. Kallikrein transduced mesenchymal stem cells protect against anti-GBM disease and lupus nephritis by ameliorating inflammation and oxidative stress[J]. PLoS One, 2013, 8: e67790.
[40] Li Y, Yan M, Yang J, et al. Glutathione S-transferase Mu 2-transduced mesenchymal stem cells ameliorated anti-glomerular basement membrane antibody-induced glomerulonephritis by inhibiting oxidation and inflammation[J]. Stem Cell Res Ther, 2014, 5: 19.
[41] Li Y, Li W, Liu C, et al. Delivering oxidation resistance-1 (OXR1) to mouse kidney by genetic modified mesenchymal stem cells exhibited enhanced protection against nephrotoxic serum induced renal injury and lupus nephritis[J]. J Stem Cell Res Ther, 2014, 4: 231.
[42] Kunter U, Rong S, Djuric Z, et al. Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis[J]. J Am Soc Nephrol, 2006, 17: 2202-2212.
[43] Tsuda H, Yamahara K, Ishikane S, et al. Allogenic fetal membrane-derived mesenchymal stem cells contribute to renal repair in experimental glomerulonephritis[J]. Am J Physiol-Renal Physiol, 2010, 299: F1004-F1013.
[44] Ornellas FM, Ramalho RJ, Fanelli C, et al. Mesenchy-mal stromal cells induce podocyte protection in the puromycin injury model[J]. Sci Rep, 2019, 9: 19604.
[45] Yang R, Zhu X, Wang J, et al. Bone marrow mesenchy-mal stem cells attenuate the progression of focal segmental glomerulosclerosis in rat models[J]. BMC Nephrology, 2018, 19: 335.
[46] Li Y, Liu Q, Ou S, et al. Research on mechanism of MAPK signal pathway induced by BMSCs for the protei-nuria of rats kidney, glomerulosclerosis and activity of RAS[J]. Eur Rev Med Pharmacol Sci, 2021, 25: 795-803.
[47] Shi Y, Xie J, Yang M, et al. Transplantation of umbilical cord mesenchymal stem cells into mice with focal seg-mental glomerulosclerosis delayed disease manifestation[J]. Ann Transl Med, 2019, 7: 383.
[48] Gregorini M, Maccario R, Avanzini MA, et al. Antineutrophil cytoplasmic antibody-associated renal vasculitis treated with autologous mesenchymal stromal cells: evaluation of the contribution of immune-mediated mechanisms[J]. Mayo Clin Proc, 2013, 88: 1174-1179.
[49] Belingheri M, Lazzari L, Parazzi V, et al. Allogeneic mesenchymal stem cell infusion for the stabilization of focal segmental glomerulosclerosis[J]. Biologicals, 2013, 41: 439-445.
[50] Makhlough A, Shekarchian S, Moghadasali R, et al. Safety and tolerability of autologous bone marrow mesenchymal stromal cells in ADPKD patients[J]. Stem Cell Res Ther, 2017, 8: 116.
[51] Makhlough A, Shekarchian S, Moghadasali R, et al. Bone marrow-mesenchymal stromal cell infusion in patients with chronic kidney disease: A safety study with 18 months of follow-up[J]. Cytotherapy, 2018, 20: 660-669.
[52] Camilleri ET, Gustafson MP, Dudakovic A, et al. Identification and validation of multiple cell surface markers of clinical-grade adipose-derived mesenchymal stromal cells as novel release criteria for good manufacturing practice-compliant production[J]. Stem Cell Res Ther, 2016, 7: 107.
[53] Abumoawad A, Saad A, Ferguson CM, et al. In a phase 1a escalating clinical trial, autologous mesenchymal stem cell infusion for renovascular disease increases blood flow and the glomerular filtration rate while reducing inflammatory biomarkers and blood pressure[J]. Kidney Int, 2020, 97: 793-804.
[54] 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[J]. Stem Cell Res Ther, 2018, 9: 312.
[55] Chun S, Choi CB, Kim MS, et al. Safety and tolerability of bone marrow-derived mesenchymal stem cells in lupus animal models and a phase I clinical trial in humans[J]. Lupus, 2022: 508120939.
[56] Naeem A, Gupta N, Naeem U, et al. A comparison of isolation and culture protocols for human amniotic mesenchymal stem cells[J]. Cell Cycle, 2022, 21: 1543-1556.
[57] Chang H, Hsu S, Chien C. Intrarenal transplantation of hypoxic preconditioned mesenchymal stem cells improves glomerulonephritis through anti-oxidation, anti-er stress, anti-inflammation, anti-apoptosis, and anti-autophagy[J]. Antioxidants, 2020, 9: 2.
[58] Jang SG, Lee J, Hong SM, et al. Metformin enhances the immunomodulatory potential of adipose-derived mesenchymal stem cells through STAT1 in an animal model of lupus[J]. Rheumatology (Oxford), 2020, 59: 1426-1438.
[59] Kunter U, Rong S, Boor P, et al. Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes[J]. J Am Soc Nephrol, 2007, 18: 1754-1764.
[60] Javorkova E, Vackova J, Hajkova M, et al. The effect of clinically relevant doses of immunosuppressive drugs on human mesenchymal stem cells[J]. Biomed Pharmacother, 2018, 97: 402-411.