Skip to main content

Advertisement

SpringerLink
Log in

Chitin powder enhances growth factor production and therapeutic effects of mesenchymal stem cells in a chronic kidney disease rat model

  • Original Article
  • Tissue Engineering / Regenerative Medicine
  • Published:
Journal of Artificial Organs Aims and scope Submit manuscript

Abstract

Previously, we fabricated a device with polylactic acid nonwoven filters and mesenchymal stem cells (MSCs), which effectively reduced urinary protein levels in a rat model of chronic kidney disease (CKD) but could not suppress CKD progression. Therefore, to improve the therapeutic effects of MSCs, in this study, we analyzed the ability of rat adipose tissue-derived MSCs (ADSCs) in contact with chitin nonwoven filters or chitin powder to produce growth factors and examined their therapeutic effect in an adriamycin (ADR)-induced CKD rat model. Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) production was significantly enhanced by ADSCs cultured in a medium containing chitin powder (C-ADSCs) compared with that by ADSCs cultured in a standard medium without chitin (N-ADSCs). However, the production of HGF and VEGF by ADSCs on chitin nonwoven filters was not significantly enhanced compared with that by the control. Intravenous C-ADSC injection significantly increased podocin expression and improved proteinuria compared with those in saline-treated CKD rats; however, no such improvements were observed in the N-ADSC-treated group. These results showed that ADSCs cultured in a medium supplemented with chitin powder suppressed proteinuria via enhanced HGF and VEGF production in ADR-induced CKD rats to mitigate podocyte damage, offering a new strategy to reduce the dose of MSC therapy for safe and effective treatment of kidney disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9:11–5. https://doi.org/10.1016/j.stem.2011.06.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sávio-Silva C, Soinski-Sousa PE, Balby-Rocha MTA, Lira ÁO, Rangel ÉB. Mesenchymal stem cell therapy in acute kidney injury (AKI): review and perspectives. Rev Assoc Med Bras. 2020;66:s45-54. https://doi.org/10.1590/1806-9282.66.S1.45.

    Article  Google Scholar 

  3. Kuppe C, Kramann R. Role of mesenchymal stem cells in kidney injury and fibrosis. Curr Opin Nephrol Hypertens. 2016;25:372–7. https://doi.org/10.1097/MNH.0000000000000230.

    Article  CAS  PubMed  Google Scholar 

  4. Griffin MD, Ryan AE, Alagesan S, Lohan P, Treacy O, Ritter T. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: what have we learned so far? Immunol Cell Biol. 2013;91:40–51. https://doi.org/10.1038/icb.2012.67.

    Article  CAS  PubMed  Google Scholar 

  5. Hori H, Iwamoto U, Niimi G, Shinzato M, Hiki Y, Tokushima Y, Kawaguchi K, Ohashi A, Nakai S, Yasutake M, Kitaguchi N. Appropriate nonwoven filters effectively capture human peripheral blood cells and mesenchymal stem cells, which show enhanced production of growth factors. J Artif Organs. 2015;18:55–63. https://doi.org/10.1007/s10047-014-0794-9.

    Article  CAS  PubMed  Google Scholar 

  6. Hori H, Shinzato M, Hiki Y, Nakai S, Niimi G, Nagao S, Kitaguchi N. Combination of nonwoven filters and mesenchymal stem cells reduced glomerulosclerotic lesions in rat chronic kidney disease models. Int J Clin Med. 2019;10:135–49. https://doi.org/10.4236/ijcm.2019.103014.

    Article  CAS  Google Scholar 

  7. Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol. 2001;12:1448–57. https://doi.org/10.1681/ASN.V1271448.

    Article  CAS  PubMed  Google Scholar 

  8. Iliescu R, Fernandez SR, Kelsen S, Maric C, Chade AR. Role of renal microcirculation in experimental renovascular disease. Nephrol Dial Transplant. 2010;25:1079–87. https://doi.org/10.1093/ndt/gfp605.

    Article  CAS  PubMed  Google Scholar 

  9. Leonard EC, Friedrich JL, Basile DP. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am J Physiol Renal Physiol. 2008;295:F1648–57. https://doi.org/10.1152/ajprenal.00099.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gong R, Rifai A, Dworkin LD. Anti-inflammatory effect of hepatocyte growth factor in chronic kidney disease: targeting the inflamed vascular endothelium. J Am Soc Nephrol. 2006;17:2464–73. https://doi.org/10.1681/ASN.2006020185.

    Article  CAS  PubMed  Google Scholar 

  11. Oka M, Sekiya S, Sakiyama R, Shimizu T, Nitta K. Hepatocyte growth factor-secreting mesothelial cell sheets suppress progressive fibrosis in a rat model of CKD. J Am Soc Nephrol. 2019;30:261–76. https://doi.org/10.1681/ASN.2018050556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Imafuku A, Oka M, Miyabe Y, Sekiya S, Nitta K, Shimizu T. Rat mesenchymal stromal cell sheets suppress renal fibrosis via microvascular protection. Stem Cells Transl Med. 2019;8:1330–41. https://doi.org/10.1002/sctm.19-0113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Singh R, Shitiz K, Singh A. Chitin and chitosan: biopolymers for wound management. Int Wound J. 2017;14:1276–89. https://doi.org/10.1111/iwj.12797.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Malafaya PB, Silva GA, Reis RL. Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv Drug Deliv Rev. 2007;59:207–33. https://doi.org/10.1016/j.addr.2007.03.012.

    Article  CAS  PubMed  Google Scholar 

  15. Peter MG. Applications and environmental aspects of chitin and chitosan. J Macromol Sci A. 1995;32:629–40. https://doi.org/10.1080/10601329508010276.

    Article  Google Scholar 

  16. Tharanathan RN, Kittur FS. Chitin–the undisputed biomolecule of great potential. Crit Rev Food Sci Nutr. 2003;43:61–87. https://doi.org/10.1080/10408690390826455.

    Article  CAS  PubMed  Google Scholar 

  17. Sum Chow K, Khor E, Andrew ChweeAun Wan. Porous chitin matrices for tissue engineering: fabrication and in vitro cytotoxic assessment. J Polym Res. 2001;8:27–35. https://doi.org/10.1007/s10965-006-0132-x.

    Article  Google Scholar 

  18. Maeda Y, Jayakumar R, Nagahama H, Furuike T, Tamura H. Synthesis, characterization and bioactivity studies of novel beta-chitin scaffolds for tissue-engineering applications. Int J Biol Macromol. 2008;42:463–7. https://doi.org/10.1016/j.ijbiomac.2008.03.002.

    Article  CAS  PubMed  Google Scholar 

  19. Madhumathi K, Sudheesh Kumar PT, Kavya KC, Furuike T, Tamura H, Nair SV, Jayakumar R. Novel chitin/nanosilica composite scaffolds for bone tissue engineering applications. Int J Biol Macromol. 2009;45:289–92. https://doi.org/10.1016/j.ijbiomac.2009.06.009.

    Article  CAS  PubMed  Google Scholar 

  20. Peter M, Sudheesh Kumar PT, Binulal NS, Nair SV, Tamura H, Jayakumar R. Development of novel α-chitin/nanobioactive glass ceramic composite scaffolds for tissue engineering applications. Carbohydr Polym. 2009;78:926–31. https://doi.org/10.1016/j.carbpol.2009.07.016.

    Article  CAS  Google Scholar 

  21. Iwamoto U, Hori H, Takami Y, Tokushima Y, Shinzato M, Yasutake M, Kitaguchi N. A novel cell-containing device for regenerative medicine: biodegradable nonwoven filters with peripheral blood cells promote wound healing. J Artif Organs. 2015;18:315–21. https://doi.org/10.1007/s10047-015-0845-x.

    Article  CAS  PubMed  Google Scholar 

  22. Song IH, Jung KJ, Lee TJ, Kim JY, Sung EG, Bae YC, Park YH. Mesenchymal stem cells attenuate adriamycin-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of the NF-kB. Nephrology (Carlton). 2018;23:483–92. https://doi.org/10.1111/nep.13047.

    Article  CAS  PubMed  Google Scholar 

  23. Da Silva CA, Chalouni C, Williams A, Hartl D, Lee CG, Elias JA. Chitin is a size-dependent regulator of macrophage TNF and IL-10 production. J Immunol. 2009;182:3573–82. https://doi.org/10.4049/jimmunol.0802113.

    Article  CAS  PubMed  Google Scholar 

  24. Crisostomo PR, Wang Y, Markel TA, Wang M, Lahm T, Meldrum DR. Human mesenchymal stem cells stimulated by TNF-alpha, LPS, or hypoxia produce growth factors by an NF kappa B- but not JNK-dependent mechanism. Am J Physiol Cell Physiol. 2008;294:C675–82. https://doi.org/10.1152/ajpcell.00437.

    Article  CAS  PubMed  Google Scholar 

  25. Bertani T, Poggi A, Pozzoni R, Delaini F, Sacchi G, Thoua Y, Mecca G, Remuzzi G, Donati MB. Adriamycin-induced nephrotic syndrome in rats: sequence of pathologic events. Lab Invest. 1982;46:16–23.

    CAS  PubMed  Google Scholar 

  26. Roselli S, Gribouval O, Boute N, Sich M, Benessy F, Attié T, Gubler MC, Antignac C. Podocin localizes in the kidney to the slit diaphragm area. Am J Pathol. 2002;160:131–9. https://doi.org/10.1016/S0002-9440(10)64357-X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhu B, Wang Y, Jardine M, Jun M, Lv JC, Cass A, Liyanage T, Chen HY, Wang YJ, Perkovic V. Tripterygium preparations for the treatment of CKD: a systematic review and meta-analysis. Am J Kidney Dis. 2013;62:515–30. https://doi.org/10.1053/j.ajkd.2013.02.374.

    Article  CAS  PubMed  Google Scholar 

  28. Taylor A, Sharkey J, Harwood R, Scarfe L, Barrow M, Rosseinsky MJ, Adams DJ, Wilm B, Murray P. Multimodal imaging techniques show differences in homing capacity between mesenchymal stromal cells and macrophages in mouse renal injury models. Mol Imaging Biol. 2020;22:904–13. https://doi.org/10.1007/s11307-019-01458-8.

    Article  CAS  PubMed  Google Scholar 

  29. Ezquer F, Giraud-Billoud M, Carpio D, Cabezas F, Conget P, Ezquer M. Proregenerative microenvironment triggered by donor mesenchymal stem cells preserves renal function and structure in mice with severe diabetes mellitus. BioMed Res Int. 2015;2015: 164703. https://doi.org/10.1155/2015/164703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dai C, Saleem MA, Holzman LB, Mathieson P, Liu Y. Hepatocyte growth factor signaling ameliorates podocyte injury and proteinuria. Kidney Int. 2010;77:962–73. https://doi.org/10.1038/ki.2010.40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zoja C, Garcia PB, Rota C, Conti S, Gagliardini E, Corna D, Zanchi C, Bigini P, Benigni A, Remuzzi G, Morigi M. Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell dysfunction in adriamycin-induced nephropathy. Am J Physiol Renal Physiol. 2012;303:F1370–81. https://doi.org/10.1152/ajprenal.00057.2012.

    Article  CAS  PubMed  Google Scholar 

  32. Sukho P, Kirpensteijn J, Hesselink JW, van Osch GJ, Verseijden F, Bastiaansen-Jenniskens YM. Effect of cell seeding density and inflammatory cytokines on adipose tissue-derived stem cells: an in vitro study. Stem Cell Rev Rep. 2017;13:267–77. https://doi.org/10.1007/s12015-017-9719-3.

    Article  CAS  PubMed  Google Scholar 

  33. Burst VR, Gillis M, Pütsch F, Herzog R, Fischer JH, Heid P, Müller-Ehmsen J, Schenk K, Fries JW, Baldamus CA, Benzing T. Poor cell survival limits the beneficial impact of mesenchymal stem cell transplantation on acute kidney injury. Nephron Exp Nephrol. 2010;114:e107–16. https://doi.org/10.1159/000262318.

    Article  PubMed  Google Scholar 

  34. He N, Zhang L, Cui J, Li Z. Bone marrow vascular niche: home for hematopoietic stem cells. Bone Marrow Res. 2014;2014: 128436. https://doi.org/10.1155/2014/128436.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mias C, Trouche E, Seguelas MH, Calcagno F, Dignat-George F, Sabatier F, Piercecchi-Marti MD, Daniel L, Bianchi P, Calise D, Bourin P, Parini A, Cussac D. Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney. Stem Cells. 2008;26:1749–57. https://doi.org/10.1634/stemcells.2007-1000.

    Article  CAS  PubMed  Google Scholar 

  36. Han YS, Kim SM, Lee JH, Jung SK, Noh H, Lee SH. Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC -dependent enhancement of the mitochondrial function. J Pineal Res. 2019;66: e12535. https://doi.org/10.1111/jpi.12535.

    Article  CAS  PubMed  Google Scholar 

  37. Han YS, Lee JH, Jung JS, Noh H, Baek MJ, Ryu JM, Yoon YM, Han HJ, Lee SH. Fucoidan protects mesenchymal stem cells against oxidative stress and enhances vascular regeneration in a murine hindlimb ischemia model. Int J Cardiol. 2015;198:187–95. https://doi.org/10.1016/j.ijcard.2015.06.070.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partially supported by Fujita Health University faculty research grant. The authors thank Mr. Rei Kondou, Mr. Tomoya Fujimoto, Mr. Yuya Higashimoto, and Mr. Hikaru Kataoka for their technical assistance, and Editage (www.editage.com) for English language editing.

Author information

Authors and Affiliations

  1. Faculty of Medical Technology, School of Medical Sciences, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan

    Hideo Hori

  2. Faculty of Clinical Engineering, School of Medical Sciences, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan

    Kazuyoshi Sakai, Atsushi Ohashi & Shigeru Nakai

Authors
  1. Hideo Hori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuyoshi Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atsushi Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shigeru Nakai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, and data collection and analysis were performed by HH, KS, AO, and SN. The first draft of the manuscript was written by HH, and all authors commented on the previous versions of the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Hideo Hori or Shigeru Nakai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hori, H., Sakai, K., Ohashi, A. et al. Chitin powder enhances growth factor production and therapeutic effects of mesenchymal stem cells in a chronic kidney disease rat model. J Artif Organs 26, 203–211 (2023). https://doi.org/10.1007/s10047-022-01346-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10047-022-01346-z

Keywords

Search

Navigation