Hideo Hori^1*, Masanori Shinzato², Yoshiyuki Hiki¹, Shigeru Nakai¹, Gen Niimi³, Shizuko Nagao⁴, Nobuya Kitaguchi¹

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¹ Faculty of Clinical Engineering, School of Health Sciences, Fujita Health University, Toyoake, Japan.
² Faculty of Medical Management & Information Science, School of Health Sciences, Fujita Health University, Toyoake, Japan.
³ Joint Research Laboratory Center for Research Promotion and Support, Fujita Health University, Toyoake, Japan.
⁴ Education and Research Facility of Animal Models for Human Diseases Center for Research Promotion and Support, Fujita Health University, Toyoake, Japan.
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Abstract: Background and Objectives: The increasing incidence of patients requiring hemodialysis has become a medical and economic problem globally; it is necessary to maintain renal glomerulus functionality to prevent the progression of chronic kidney disease. As a therapeutic tool for preventing the progression of chronic kidney disease, mesenchymal stem cells (MSCs) are a promising source of both growth factors and cells for regeneration. However, the escape of MSCs from injection sites, as well as the insufficient production of growth factors, is issues that remain unresolved. In the present study, a complex of cells and a nonwoven filter was localized in an injured kidney to provide growth factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). Methods and Results: Nonwoven biodegradable polylactic acid (PLA) filters were used to capture rat bone marrow stem cells (r-BMSCs). The capture rates of r-BMSCs on five PLA filter disks were over 85%. The production of HGF by r-BMSCs on PLA filters was markedly enhanced through interactions between the cells and the nonwoven filter. Conversely, the production of VEGF by r-BMSC on PLA filters was unchanged. Complexes of nonwoven filters and cells were implanted onto the surfaces of kidneys of 5/6-nephrectomized rats, which are characterized by progressive glomerulosclerosis. Within the r-BMSC/PLA complexes, deleterious changes in serum creatinine levels were not attenuated. However, PLA filters with r-BMSCs, which enhanced HGF production over 4 weeks of culture, significantly (P = 0.03) decreased urinary protein levels at 4 weeks after implantation compared to untreated nephrectomized rats. Further histopathological studies revealed that glomerulosclerotic lesions were significantly (P = 0.008) reduced by treatment with the r-BMSC/PLA complex. Conclusion: Devices made of PLA nonwoven filters and stem cells are potentially useful for the prevention and treatment of chronic kidney disease.

Keywords: Nonwoven Filter, Mesenchymal Stem Cell, Hepatocyte Growth Factor, Regenerative Medicine, Chronic Kidney Disease

Cite this paper: Hori, H. , Shinzato, M. , Hiki, Y. , Nakai, S. , Niimi, G. , Nagao, S. and Kitaguchi, N. (2019) Combination of Nonwoven Filters and Mesenchymal Stem Cells Reduced Glomerulosclerotic Lesions in Rat Chronic Kidney Disease Models. International Journal of Clinical Medicine, 10, 135-149. doi: 10.4236/ijcm.2019.103014.

References

[1]   Liyanage, T., Ninomiya, T., Jha, V., Neal, B., Patrice, H.M., Okpechi, I., et al. (2015) Worldwide Access to Treatment for End-Stage Kidney Disease: A Systematic Review. The Lancet, 385, 1975-1982.
https://doi.org/10.1016/S0140-6736(14)61601-9

[2]   Just, P.M., Riella, M.C., Tschosik, E.A., Noe, L.L., Bhattacharyya, S.K. and de Charro, F. (2008) Economic Evaluations of Dialysis Treatment Modalities. Health Policy, 86, 163-180.
https://doi.org/10.1016/j.healthpol.2007.12.004

[3]   Mizuno, S., Kurosawa, T., Matsumoto, K., Mizuno-Horikawa, Y., Okamoto, M. and Nakamura, T. (1998) Hepatocyte Growth Factor Prevents Renal Fibrosis and Dysfunction in a Mouse Model of Chronic Renal Disease. The Journal of Clinical Investigation, 101, 1827-1834.
https://doi.org/10.1172/JCI1709

[4]   Flaquer, M., Romagnani, P. and Cruzado, J.M. (2010) Growth Factors and Renal Regeneration. Nefrologia, 30, 385-393.

[5]   Shimizu, A., Masuda, Y., Mori, T., Kitamura, H., Ishizaki, M., Sugisaki, Y., et al. (2004) Vascular Endothelial Growth Factor165 Resolves Glomerular Inflammation and Accelerates Glomerular Capillary Repair in Rat Anti-Glomerular Basement Membrane Glomerulonephritis. Journal of the American Society of Nephrology, 15, 2655-2665.
https://doi.org/10.1097/01.ASN.0000141038.28733.F2

[6]   Gong, R., Rifai, A., Tolbert, E.M., Biswas, P., Centracchio, J.N. and Dworkin, L.D. (2004) Hepatocyte Growth Factor Ameliorates Renal Interstitial Inflammation in Rat Remnant Kidney by Modulating Tubular Expression of Macrophage Chemoattractant Protein-1 and RANTES. Journal of the American Society of Nephrology, 15, 2868-2881.
https://doi.org/10.1097/01.ASN.0000141962.44300.3A

[7]   Yang, J., Chen, S., Huang, L., Michalopoulos, G.K. and Liu, Y. (2001) Sustained Expression of Naked Plasmid DNA Encoding Hepatocyte Growth Factor in Mice Promotes Liver and Overall Body Growth. Hepatology, 33, 848-859.
https://doi.org/10.1053/jhep.2001.23438

[8]   Ezquer, F., Ezquer, M., Simon, V., Pardo, F., Yañez, A., Carpio, D., et al. (2009) Endovenous Administration of Bone-Marrow-Derived Multipotent Mesenchymal Stromal Cells Prevents Renal Failure in Diabetic Mice. Biology of Blood and Marrow Transplantation, 15, 1354-1365.
https://doi.org/10.1016/j.bbmt.2009.07.022

[9]   Zoja, C., Garcia, P.B., Rota, C., Conti, S., Gagliardini, E., Corna, D., et al. (2012) Mesenchymal Stem Cell Therapy Promotes Renal Repair by Limiting Glomerular Podocyte and Progenitor Cell Dysfunction in Adriamycin-Induced Nephropathy. American Journal of Physiology—Renal Physiology, 303, F1370-F1381.
https://doi.org/10.1152/ajprenal.00057.2012

[10]   Semedo, P., Correa-Costa, M., Cenedeze, M.A., Malheiros, D.M.A.C., dos Reis, M.A. and Shimizu M.H. (2009) Mesenchymal Stem Cells Attenuate Renal Fibrosis through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model. Stem Cells, 27, 3063-3073.
https://doi.org/10.1002/stem.214

[11]   Song, I.H., Jung, K.J., Lee, T.J., Kim, J.Y., Sung, E.G., Bae, Y.C., et al. (2018) Mesenchymal Stem Cells Attenuate Adriamycin-Induced Nephropathy by Diminishing Oxidative Stress and Inflammation via Downregulation of the NF-kB. Nephrology, 23, 483-492.
https://doi.org/10.1111/nep.13047

[12]   Schrepfer, S., Deuse, T., Reichenspurner, H., Fischbein, M.P., Robbins, R.C. and Pelletier, M.P. (2007) Stem Cell Transplantation: The Lung Barrier. Transplantation Proceedings, 39, 573-576.
https://doi.org/10.1016/j.transproceed.2006.12.019

[13]   Hori, H., Iwamoto, U., Niimi, G., Shinzato, M., Hiki, Y., Tokushima, Y., et al. (2015) Appropriate Nonwoven Filters Effectively Capture Human Peripheral Blood Cells and Mesenchymal Stem cells, Which Show Enhanced Production of Growth Factors. Journal of Artificial Organs, 18, 55-63.
https://doi.org/10.1007/s10047-014-0794-9

[14]   Iwamoto, U., Hori, H., Takami, Y., Tokushima, Y., Shinzato, M., Yasutake, M., et al. (2015) A Novel Cell-Containing Device for Regenerative Medicine: Biodegradable Nonwoven Filters with Peripheral Blood Cells Promote Wound Healing. Journal of Artificial Organs, 18, 315-321.
https://doi.org/10.1007/s10047-015-0845-x

[15]   Shimamura, T. and Morrison, A.B. (1975) A Progressive Glomerulosclerosis Occurring in Partial Five-Sixths Nephrectomized Rats. The American Journal of Pathology, 79, 95-106.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1913032/

[16]   Caplan, A.I. and Dennis, J.E. (2006) Mesenchymal Stem Cells as Trophic Mediators. Journal of Cellular Biochemistry, 98, 1076-1084.
https://doi.org/10.1002/jcb.20886

[17]   Lv, S., Cheng, J., Sun, A., Li, J., Wang, W., Guan, G., et al. (2014) Mesenchymal Stem Cells Transplantation Ameliorates Glomerular Injury in Streptozotocin-Induced Diabetic Nephropathy in Rats via Inhibiting Oxidative Stress. Diabetes Research and Clinical Practice, 104, 143-154.
https://doi.org/10.1016/j.diabres.2014.01.011

[18]   Matsumoto, K. and Nakamura, T. (2001) Hepatocyte Growth Factor: Renotropic Role and Potential Therapeutics for Renal Diseases. Kidney International, 59, 2023-2038.
https://doi.org/10.1046/j.1523-1755.2001.00717.x

[19]   Cantaluppi, V., Biancone, L., Quercia, A., Deregibus, M.C., Segoloni, G. and Camussi, G. (2013) Rationale of Mesenchymal Stem Cell Therapy in Kidney Injury. American Journal of Kidney Diseases, 61, 300-309.
https://doi.org/10.1053/j.ajkd.2012.05.027

[20]   Ding, J., Chen, B., Lv, T., Liu, X., Fu, X., Wang, Q., et al. (2016) Bone Marrow Mesenchymal Stem Cell-Based Engineered Cartilage Ameliorates Polyglycolic Acid/Polylactic Acid Scaffold-Induced Inflammation through M2 Polarization of Macrophages in a Pig Model. Stem Cells Translational Medicine, 5, 1079-1089.
https://doi.org/10.5966/sctm.2015-0263

[21]   Ramot, Y., Haim-Zada, M., Domb, A.J. and Nyska, A. (2016) Biocompatibility and Safety of PLA and Its Copolymers. Advanced Drug Delivery Reviews, 107, 153-162.
https://doi.org/10.1016/j.addr.2016.03.012

[22]   McNally, A.K. and Anderson, J.M. (2003) Foreign Body-Type Multinucleated Giant Cell Formation Is Potently Induced by Alpha-Tocopherol AND Prevented by the Diacylglycerol Kinase Inhibitor R59022. The American Journal of Pathology, 163, 1147-1156.
https://doi.org/10.1016/S0002-9440(10)63474-8