间充质干细胞治疗糖尿病肾病的研究进展
Development of Mesenchymal Stem Cells for Treatment of Diabetic Kidney Disease
DOI: 10.12677/OJNS.2021.91014, PDF,   
作者: 赵良宇, 孟美圻, 马翠卿*：河北医科大学免疫教研室，河北省重大疾病免疫机制及干预重点实验室，河北 石家庄
关键词: 糖尿病肾病；间充质干细胞；旁分泌；外泌体；Diabetic Kidney Disease (DKD)； Mesenchymal Stem Cells (MSCs)； Paracrine； Exosomes
摘要: 糖尿病是目前危害人类健康的重大疾病，并且会引发一系列严重的并发症，其中糖尿病肾病是一种严重的微血管并发症，是各种终末期肾病的主要原因之一，缺乏相应治疗靶点，治疗效果不佳。间充质干细胞(MSCs)是一类具有自我复制和多向分化能力的细胞，MSCs移植具有直接修复肾细胞损伤、调节炎症和免疫反应、抗纤维化等功能，其对糖尿病肾病的治疗展现出了令人欣喜的成果。本文对间充质干细胞对糖尿病肾病的治疗进行综述，为间充质干细胞治疗糖尿病治疗提供新的策略。
Abstract: Diabetes is a major disease endangering human health, and it will cause a series of serious complications. Diabetic kidney disease (DKD) is a serious microvascular complication, which is one of the main causes of various end-stage renal diseases (ESRD). It lacks corresponding therapeutic targets and has poor therapeutic effect. Mesenchymal stem cells (MSCs) are a kind of cells with the ability of self-replication and multi-directional differentiation. MSCs transplantation can directly repair renal cell injury, regulate inflammation and immune response, and anti-fibrosis. The treatment of diabetic nephropathy has shown gratifying results. This paper reviews the treatment of diabetic nephropathy by MSCs, and provides a new strategy for the treatment of diabetes mellitus with MSCs.
文章引用：赵良宇, 孟美圻, 马翠卿. 间充质干细胞治疗糖尿病肾病的研究进展[J]. 自然科学, 2021, 9(1): 105-111. https://doi.org/10.12677/OJNS.2021.91014

参考文献

[1] International Diabetes Federation (2019) Diabetes Atlas 9th Edition. https://diabetesatlas.org/en/
[2] Gabr, M.M., Za-karia, M.M., Refaie, A.F., Khater, S.M., Ashamallah, S.A., Ismail, A.M., et al. (2015) Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells into Insulin-Producing Cells: Evidence for Further Maturation in Vivo. Bio-Med Research International, 2015, Article ID: 575837. [Google Scholar] [CrossRef] [PubMed]
[3] Hayashi, T., Takai S. and Yamashita, C. (2010) Impact of the Renin-Angiotensin-Aldosterone-System on Cardiovascular and Renal Complications in Diabetes Mellitus. Current Vascular Pharmacology, 8, 189-197. [Google Scholar] [CrossRef] [PubMed]
[4] Vargas, S.L., Toma, I., Kang, J.J., Meer, E.J. and Peti-Peterdi, J. (2009) Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release. Journal of the American Society of Nephrology, 20, 1002-1011. [Google Scholar] [CrossRef] 
[5] Wolf, G., Mueller, E., Stahl, R.A. and Ziyadeh, F.N. (1993) Angi-otensin II-Induced Hypertrophy of Cultured Murine Proximal Tubular Cells Is Mediated by Endogenous Transforming Growth Factor-Beta. Journal of Clinical Investigation, 92, 1366-1372. [Google Scholar] [CrossRef] 
[6] Ka-linyak, J.E., Sechi, L.A., Griffin, C.A., Don, B.R., Tavangar, K., Kraemer, F.B., et al. (1993) The Renin-Angiotensin System in Streptozotocin-Induced Diabetes Mellitus in the Rat. Journal of the American Society of Nephrology, 4, 1337-1345.
[7] Tesch, G.H., (2008) MCP-1/CCL2: A New Diagnostic Marker and Therapeutic Target for Progressive Renal Injury in Diabetic Nephropathy. American Journal of Physiology-Renal Physiology, 294, F697-F701. [Google Scholar] [CrossRef] [PubMed]
[8] Wada, T., Yokoyama, H., Matsushima, K. and Kobayashi, K. (2003) Monocyte Chemoattractant Protein-1: Does It Play a Role in Diabetic Nephropathy? Nephrology Dialysis Trans-plantation, 18, 457-459. [Google Scholar] [CrossRef] [PubMed]
[9] Yadav, A., Vallabu, S., Arora, S., Tandon, P., Slahan, D., Teichberg, S., et al. (2010) ANG II Promotes Autophagy in Podocytes. American Journal of Physiology-Cell Physiology, 299, C488-C496. [Google Scholar] [CrossRef] [PubMed]
[10] Sun, L. and Kanwar, Y.S. (2015) Relevance of TNF-Alpha in the Context of Other Inflammatory Cytokines in the Progression of Diabetic Nephropathy. Kidney International, 88, 662-665. [Google Scholar] [CrossRef] [PubMed]
[11] Di Paolo, S., Gesualdo, L, Ranieri, E, Grandaliano, G, Schena, F.P. (1996) High Glucose Concentration Induces the Overexpression of Transforming Growth Factor-Beta through the Acti-vation of a Platelet-Derived Growth Factor Loop in Human Mesangial Cells. The American Journal of Pathology, 149, 2095-2106.
[12] Noh, H. and King, G.L. (2007) The Role of Protein Kinase C Activation in Diabetic Nephropathy. Kidney International, 2007, S49-S53. [Google Scholar] [CrossRef] [PubMed]
[13] Derubertis, F.R. and Craven, P.A. (1994) Activation of Protein Kinase C in Glomerular Cells in Diabetes. Mechanisms and Potential Links to the Patho-genesis of Diabetic Glomerulopathy. Diabetes, 43, 1-8. [Google Scholar] [CrossRef] [PubMed]
[14] Rodriguez-Iturbe, B., Pons, H., Herrera-Acosta, J. and Johnson, R.J. (2001) Role of Immunocompotent Cells in Nonimmune Renal Diseases. Kidney International, 59, 1626-1640. [Google Scholar] [CrossRef] [PubMed]
[15] Griffin, M.D., Elliman, S.J., Cahill, E., English, K., Ceredig, R. and Ritter, T. (2013) Concise Review: Adult mesenchymal stromal Cell Therapy for Inflammatory Diseases: How Well Are We Joining the Dots? Stem Cells, 31, 2033-2041. [Google Scholar] [CrossRef] [PubMed]
[16] Li, H., Rong, P.F., Ma, X.Q., Nie, W., Chen, Y., Zhang, J., et al. (2020) Mouse Umbilical Cord Mesenchymal Stem Cell Paracrine Alleviates Renal Fibrosis in Diabetic Nephropathy by Reduc-ing Myofibroblast Transdifferentiation and Cell Proliferation and Upregulating MMPs in Mesangial Cells. Journal of Diabetes Research, 2020, Article ID: 3847171. [Google Scholar] [CrossRef] [PubMed]
[17] Xiang, E., et al. (2020) Human Umbilical Cord-Derived Mesenchymal Stem Cells Prevent the Progression of Early Diabetic Nephropathy through Inhibiting Inflammation and Fibrosis. Stem Cell Research & Therapy, 11, 336.
[18] Herrera, M.B., Bussolati, B., Bruno, S., Fonsato, V., Romanazzi, G.M. and Camussi, G. (2004) Mesenchymal Stem Cells Contribute to the Renal Repair of Acute Tubular Epithelial Injury. Interna-tional Journal of Molecular Medicine, 14, 1035-1041. [Google Scholar] [CrossRef] 
[19] Gili, M., Orsello, A., Gallo, S. and Brizzi, M.F. (2013) Diabetes-Associated Macrovascular Complications: Cell-Based Therapy a New Tool? Endocrine, 44, 557-575. [Google Scholar] [CrossRef] [PubMed]
[20] Ezquer, F., Giraud-Billoud, M., Carpio, D., Cabezas, F., Conget, P., and Ezquer, M. (2015) Proregenerative Microenvironment Triggered by Donor Mesenchymal Stem Cells Preserves Renal Function and Structure in Mice with Severe Diabetes Mellitus. BioMed Re-search International, 2015, Article ID: 164703. [Google Scholar] [CrossRef] [PubMed]
[21] Kuroda, Y., Kitada, M., Wakao, S. and Dezawa, M (2011) Bone Mar-row Mesenchymal Cells: How Do They Contribute to Tissue Repair and Are They Really Stem Cells? Archivum Immu-nologiae et Therapiae Experimentalis, 59, Article No. 369. [Google Scholar] [CrossRef] [PubMed]
[22] Massee, M., Chinn, K., Lim, J.J., Godwin, L., Young, C.S. and Koob, T.J. (2016) Type I and II Diabetic Adipose-Derived Stem Cells Respond In Vitro to Dehydrated Human Amni-on/Chorion Membrane Allograft Treatment by Increasing Proliferation, Migration, and Altering Cytokine Secretion. Ad-vances in Wound Care, 5, 43-54. [Google Scholar] [CrossRef] [PubMed]
[23] Yuan, Y.J., Shi, M.M., Li, L., Liu, J.P., Chen, B., Chen, Y.N., et al. (2016) Mesenchymal Stem Cell-Conditioned Media Ameliorate Diabetic Endothelial Dysfunction by Improving Mi-tochondrial Bioenergetics via the Sirt1/AMPK/PGC -1α Pathway. Clinical Science (London), 130, 2181-2198. [Google Scholar] [CrossRef] 
[24] Biancone, L., Bruno, S., Deregibus, M.C., Tetta, C. and Camussi, G. (2012) Therapeutic Potential of Mesenchymal Stem Cell-Derived Microvesicles. Nephrology Dialysis Transplantation, 27, 3037-3042. [Google Scholar] [CrossRef] [PubMed]
[25] Gnecchi, M., Danieli, P., Malpasso, G. and Ciuffreda, M.C. (2016) Para-crine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. In: Gnecchi, M., Ed., Mesenchymal Stem Cells, Vol. 1416, Humana Press, New York, 123-146. [Google Scholar] [CrossRef] [PubMed]
[26] Motazed, R., Colville-Nash, P., Kwan, J.T.C. and Dockrell, M.E.C. (2008) BMP-7 and Proximal Tubule Epithelial Cells: Activation of Multiple Signaling Pathways Reveals a Novel Anti-Fibrotic Mechanism. Pharmaceutical Research, 25, 2440-2446. [Google Scholar] [CrossRef] [PubMed]
[27] Luo, D.D., Phillips, A. and Fraser, D. (2010) Bone Morphoge-netic Protein-7 Inhibits Proximal Tubular Epithelial Cell Smad3 Signaling via Increased SnoN Expression. The American Journal of Pathology, 176, 1139-1147. [Google Scholar] [CrossRef] [PubMed]
[28] Lv, S., Liu, G., Sun, A.L., Wang, J.P., Cheng, J., Wang, W.W., et al. (2014) Mesenchymal Stem Cells Ameliorate Diabetic Glomerular Fibrosis in Vivo and in Vitro by Inhibiting TGF-Beta Signalling via Secretion of Bone Morphogenetic Protein 7. Diabetes and Vascular Disease Research, 11, 251-261. [Google Scholar] [CrossRef] [PubMed]
[29] Lv, S.S., Liu, G., Wang, J.P., Wang, W.-W., Cheng, J., Sun, A.L., et al. (2013) Mesenchymal Stem Cells Transplantation Ameliorates Glomerular Injury in Streptozoto-cin-Induced Diabetic Nephropathy in Rats via Inhibiting Macrophage Infiltration. International Immunopharmacology, 17, 275-282. [Google Scholar] [CrossRef] [PubMed]
[30] Li, D.G., Wang, N., Zhang, L., Zhu, H.Y., Bai, X.Y., Bo, F., et al. (2013) Mesenchymal Stem Cells Protect Podocytes from Apoptosis Induced by High Glucose via Secretion of Epithelial Growth Factor. Stem Cell Research & Therapy, 4, Article No. 103. [Google Scholar] [CrossRef] [PubMed]
[31] 张玮, 彭澎, 沈铿. 外泌体来源RNA在细胞通讯中的作用[J]. 中国医学科学院学报, 2016, 38(4): 480-483.
[32] Bruno, S., Porta, S. and Bussolati, B. (2016) Extracellular Vesicles in Renal Tissue Damage and Regeneration. European Journal of Pharmacology, 790, 83-91. [Google Scholar] [CrossRef] [PubMed]
[33] Jiang, Z.Z., Liu Y.-M., Niu, X., Yin, J.-Y., Hu, B., Guo, S.-C., et al. (2016) Exosomes Secreted by Human Urine-Derived Stem Cells Could Prevent Kidney Complications from Type I Diabetes in Rats. Stem Cell Research & Therapy, 7, Article No. 24. [Google Scholar] [CrossRef] [PubMed]
[34] Jin, J., Shi, Y.F., Gong, J.G., Zhao, L., Li, Y.W., He, Q. and Huang, H. (2019) Exosome Secreted from Adipose-Derived Stem Cells Attenuates Diabetic Nephropathy by Promoting Autophagy Flux and Inhibiting Apoptosis in Podocyte. Stem Cell Research & Therapy, 10, Article No. 95. [Google Scholar] [CrossRef] [PubMed]
[35] Nagaishi, K., Mizue, Y., Chikenji, T., Otani, M., Nakano, M., Konari, N., et al. (2016) Mesenchymal Stem Cell Therapy Ameliorates Diabetic Nephropathy via the Paracrine Effect of Renal Trophic Factors Including Exosomes. Scientific Reports, 6, Article No. 34842. [Google Scholar] [CrossRef] [PubMed]
[36] Ebrahim, N., Ahmed, I.A., Hussien, N.I., Dessouky, A.A., Farid, A.S., Elshazly, A.M., et al. (2018) Mesenchymal Stem Cell-Derived Exosomes Ameliorated Diabetic Nephropathy by Au-tophagy Induction through the mTOR Signaling Pathway. Cells, 7, 226. [Google Scholar] [CrossRef] [PubMed]
[37] Wong, C.Y., Tan, E.L. and Cheong, S.K. (2014) In vitro Differentiation of Mesenchymal Stem Cells into Mesangial Cells When Co-Cultured with Injured Mesangial Cells. Cell Biology Interna-tional, 38, 497-501. [Google Scholar] [CrossRef] [PubMed]
[38] Chamberlain, G., Fox, J., Ashton, B. and Middleton, J. (2007) Concise Review: Mesenchymal Stem Cells: Their Phenotype, Differentiation Capacity, Immunological Features, and Potential for Homing. Stem Cells, 25, 2739-2749. [Google Scholar] [CrossRef] [PubMed]
[39] Cai, X.J., Wang, L., Wang, X.L., Hou, F. (2020) miR-124a En-hances Therapeutic Effects of Bone Marrow Stromal Cells Transplant on Diabetic Nephropathy-Related Epitheli-al-to-Mesenchymal Transition and Fibrosis. Journal of Cellular Biochemistry, 121, 299-312. [Google Scholar] [CrossRef] [PubMed]
[40] Duan, Y.R., Luo, Q.Y., Wang, Y., Ma, Y.L., Chen, F., Zhu, X.G., et al. (2020) Adipose Mesenchymal Stem Cell-Derived Extracellular Vesicles Containing MicroRNA-26a-5p Target TLR4 and Protect against Diabetic Nephropathy. Journal of Biological Chemistry, 295, 12868-12884.
[41] Wang, S., Li, Y., Zhao, J.H., Zhang, J.B. and Huang, Y.J. (2013) Mesenchymal Stem Cells Ameliorate Podocyte Injury and Proteinuria in a Type 1 Diabetic Nephropathy Rat Model. Biol Blood Marrow Transplant, 19, 538-546. [Google Scholar] [CrossRef] [PubMed]
[42] Musial-Wysocka, A., Kot, M. and Majka, M. (2019) The Pros and Cons of Mesenchymal Stem Cell-Based Therapies. Cell Transplant, 28, 801-812. [Google Scholar] [CrossRef] [PubMed]
[43] Kunter, U., Rong, S., Boor, P., Eitner, F., Müller-Newen, G., Djuric, Z., et al. (2007) Mesenchymal Stem Cells Prevent Progressive Experimental Renal Failure but Maldifferentiate into Glomerular Adipocytes. Journal of the American Society of Nephrology, 18, 1754-1764. [Google Scholar] [CrossRef]