Abstract
Background:
Immunoglobulin A (IgA) nephropathy (IgAN) is one of an important cause of progressive kidney disease and occurs when IgA settles in the kidney resulted in disrupts kidney’s ability to filter waste and excess water. Hydrogels are promising material for medical applications owing to their excellent adaptability and filling ability. Herein, we proposed a hyaluronic acid/gelatin (CHO-HA/Gel-NH2) bioactive hydrogel as a cell carrier for therapeutic kidney regeneration in IgAN.
Methods:
CHO-HA/Gel-NH2 hydrogel was fabricated by Schiff-base reaction without any additional crosslinking agents. The hydrogel concentrations and ratios were evaluated to enhance adequate mechanical properties and biocompatibility for further in vivo study. High serum IgA ddY mice kidneys were treated with human urine-derived renal progenitor cells encapsulated in the hydrogel to investigate the improvement of IgA nephropathy and kidney regeneration.
Results:
The stiffness of the hydrogel was significantly enhanced and could be modulated by altering the concentrations and ratios of hydrogel. CHO-HA/Gel-NH2 at a ratio of 3/7 provided a promising milieu for cells viability and cells proliferation. From week four onwards, there was a significant reduction in blood urea nitrogen and serum creatinine level in Cell/Gel group, as well as well-organized glomeruli and tubules. Moreover, the expression of pro-inflammatory and pro-fibrotic molecules significantly decreased in the Gel/Cell group, whereas anti-inflammatory gene expression was elevated compared to the Cell group.
Conclusion:
Based on in vivo studies, the renal regenerative ability of the progenitor cells could be further increased by this hydrogel system.
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References
Rodrigues JC, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol. 2017;12:677–86.
Yeo SC, Cheung CK, Barratt J. New insights into the pathogenesis of IgA nephropathy. Pediatr Nephrol. 2018;33:763–77.
Chou YH, Pan SY, Yang CH, Lin SL. Stem cells and kidney regeneration. J Formos Med Assoc. 2014;113:201–9.
Liu D, Cheng F, Pan S, Liu Z. Stem cells: a potential treatment option for kidney diseases. Stem Cell Res Ther. 2020;11:249.
Hyun YY, Kim IO, Kim MH, Nam DH, Lee MH, Kim JE, et al. Adipose-derived stem cells improve renal function in a mouse model of IgA nephropathy. Cell Transplant. 2012;21:2425–39.
Rota C, Morigi M, Imberti B. Stem cell therapies in kidney diseases: progress and challenges. Int J Mol Sci. 2019;20:2790.
Ribeiro PC, Lojudice FH, Fernandes-Charpiot IMM, Baptista MASF, de Almeida Araújo S, Mendes GEF, et al. Therapeutic potential of human induced pluripotent stem cells and renal progenitor cells in experimental chronic kidney disease. Stem Cell Res Ther. 2020;11:530.
Burdeyron P, Giraud S, Hauet T, Steichen C. Urine-derived stem/progenitor cells: a focus on their characterization and potential. World J Stem Cells. 2020;12:1080–96.
Lazzeri E, Ronconi E, Angelotti ML, Peired A, Mazzinghi B, Becherucci F, et al. Human urine-derived renal progenitors for personalized modeling of genetic kidney disorders. J Am Soc Nephrol. 2015;26:1961–74.
Kim IL, Mauck RL, Burdick JA. Hydrogel design for cartilage tissue engineering: a case study with hyaluronic acid. Biomaterials. 2011;32:8771–82.
Khunmanee S, Jeong Y, Park H. Crosslinking method of hyaluronic-based hydrogel for biomedical applications. J Tissue Eng. 2017;8:2041731417726464.
Martínez-Sanz E, Ossipov DA, Hilborn J, Larsson S, Jonsson KB, Varghese OP. Bone reservoir: injectable hyaluronic acid hydrogel for minimal invasive bone augmentation. J Control Release. 2011;152:232–40.
Kim DY, Park H, Kim SW, Lee JW, Lee KY. Injectable hydrogels prepared from partially oxidized hyaluronate and glycol chitosan for chondrocyte encapsulation. Carbohydr Polym. 2017;157:1281–7.
Zhang L, Li K, Xiao W, Zheng L, Xiao Y, Fan H, et al. Preparation of collagen–chondroitin sulfate–hyaluronic acid hybrid hydrogel scaffolds and cell compatibility in vitro. Carbohydr Polym. 2011;84:118–25.
Vahedi M, Barzin J, Shokrolahi F, Shokrollahi P. Self-healing, injectable gelatin hydrogels cross-linked by dynamic schiff base linkages support cell adhesion and sustained release of antibacterial drugs. Macromol Mater Eng. 2018;303:1800200.
Jalalvandi E, Hanton LR, Moratti SC. Schiff-base based hydrogels as degradable platforms for hydrophobic drug delivery. Eur Polym J. 2017;90:13–24.
Malik US, Niazi MBK, Jahan Z, Zafar MI, Vo DVN, Sher F. Nano-structured dynamic Schiff base cues as robust self-healing polymers for biomedical and tissue engineering applications: a review. Environ Chem Lett. 2021;20:495–517.
Wang X, He J, Wang Y, Cui FZ. Hyaluronic acid-based scaffold for central neural tissue engineering. Interface Focus. 2012;2:278–91.
Xu X, Jha AK, Harrington DA, Farach-Carson MC, Jia X. Hyaluronic acid-based hydrogels: from a natural polysaccharide to complex networks. Soft Matter. 2012;8:3280–94.
Burdick JA, Prestwich GD. Hyaluronic acid hydrogels for biomedical applications. Adv Mater. 2011;23:H41–56.
Hozumi T, Kageyama T, Ohta S, Fukuda J, Ito T. Injectable hydrogel with slow degradability composed of gelatin and hyaluronic acid cross-linked by Schiff’s base formation. Biomacromolecules. 2018;19:288–97.
Yang G, Xiao Z, Ren X, Long H, Qian H, Ma K, et al. Enzymatically crosslinked gelatin hydrogel promotes the proliferation of adipose tissue-derived stromal cells. PeerJ. 2016;4:e2497.
Sakai S, Ohi H, Taya M. Gelatin/hyaluronic acid content in hydrogels obtained through blue light-induced gelation affects hydrogel properties and adipose stem cell behaviors. Biomolecules. 2019;9:342.
Poveda-Reyes S, Moulisova V, Sanmartín-Masiá E, Quintanilla-Sierra L, Salmerón-Sánchez M, Ferrer GG. Gelatin—hyaluronic acid hydrogels with tuned stiffness to counterbalance cellular forces and promote cell differentiation. Macromol Biosci. 2016;16:1311–24.
Le Thi P, Son JY, Lee Y, Ryu SB, Park KM, Park KD. Enzymatically crosslinkable hyaluronic acid-gelatin hybrid hydrogels as potential bioinks for tissue regeneration. Macromol Res. 2020;28:400–6.
Joo H, Park J, Sutthiwanjampa C, Kim H, Bae T, Kim W, et al. Surface coating with hyaluronic acid-gelatin-crosslinked hydrogel on gelatin-conjugated poly(dimethylsiloxane) for implantable medical device-induced fibrosis. Pharmaceutics. 2021;13:269.
Tan H, Rubin JP, Marra KG. Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for adipose tissue regeneration. Organogenesis. 2010;6:173–80.
Fan M, Zhang Z, Mao J, Tan H. Injectable multi-arm poly(ethylene glycol)/hyaluronic acid hydrogels for adipose tissue engineering. J Macromol Sci A. 2015;52:345–52.
Wei Z, Zhao J, Chen YM, Zhang P, Zhang Q. Self-healing polysaccharide-based hydrogels as injectable carriers for neural stem cells. Sci Rep. 2016;6:37841.
Li NN, Fu CP, Zhang LM. Using casein and oxidized hyaluronic acid to form biocompatible composite hydrogels for controlled drug release. Mater Sci Eng C Mater Biol Appl. 2014;36:287–93.
Lopez-Cebral R, Martín-Pastor M, Evelin Parraga J, Konat Zorzi G, Seijo B, Sanchez A. Chemically modified gelatin as biomaterial in the design of new nanomedicines. Med Chem. 2011;7:145–54.
Wu F, Pang Y, Liu J. Swelling-strengthening hydrogels by embedding with deformable nanobarriers. Nat Commun. 2020;11:4502.
Gao WW, Zheng J, Yun W, Kang PJ, Park G, Song G, et al. Generation of induced nephron progenitor-like cells from human urine-derived cells. Int J Mol Sci. 2021;22:13449.
Li L, Wang N, Jin X, Deng R, Nie S, Sun L, et al. Biodegradable and injectable in situ cross-linking chitosan-hyaluronic acid based hydrogels for postoperative adhesion prevention. Biomaterials. 2014;35:3903–17.
Amonpattaratkit P, Khunmanee S, Kim DH, Park H. Synthesis and characterization of gelatin-based crosslinkers for the fabrication of superabsorbent hydrogels. Materials (Basel). 2017;10:826.
Sanmartín-Masiá E, Poveda-Reyes S, Gallego Ferrer G. Extracellular matrix–inspired gelatin/hyaluronic acid injectable hydrogels. Int J Polym Mater. 2017;66:280–8.
Liu M, Li W, Rong J, Zhou C. Novel polymer nanocomposite hydrogel with natural clay nanotubes. Colloid Polym Sci. 2012;290:895–905.
Moura MJ, Figueiredo MM, Gil MH. Rheological study of genipin cross-linked chitosan hydrogels. Biomacromolecules. 2007;8:3823–9.
Sarker A, Amirian J, Min YK, Lee BT. HAp granules encapsulated oxidized alginate–gelatin–biphasic calcium phosphate hydrogel for bone regeneration. Int J Biol Macromol. 2015;81:898–911.
Zhang F, He C, Cao L, Feng W, Wang H, Mo X, et al. Fabrication of gelatin–hyaluronic acid hybrid scaffolds with tunable porous structures for soft tissue engineering. Int J Biol Macromol. 2011;48:474–81.
Gupta B, Tummalapalli M, Deopura BL, Alam MS. Preparation and characterization of in-situ crosslinked pectin–gelatin hydrogels. Carbohydr Polym. 2014;106:312–8.
Nair S, Remya NS, Remya S, Nair PD. A biodegradable in situ injectable hydrogel based on chitosan and oxidized hyaluronic acid for tissue engineering applications. Carbohydr Polym. 2011;85:838–44.
Rodrigues WF, Miguel CB, Napimoga MH, Oliveira CF, Lazo-Chica JE. Establishing standards for studying renal function in mice through measurements of body size-adjusted creatinine and urea levels. Biomed Res Int. 2014;2014:872827.
Jamshidzadeh A, Heidari R, Mohammadi-Samani S, Azarpira N, Najbi A, Jahani P, et al. A comparison between the nephrotoxic profile of gentamicin and gentamicin nanoparticles in mice. J Biochem Mol Toxicol. 2015;29:57–62.
Ramesh G, Reeves WB. Inflammatory cytokines in acute renal failure. Kidney Int Suppl. 2004;66:S56–61.
Black LM, Lever JM, Agarwal A. Renal inflammation and fibrosis: a double-edged sword. J Histochem Cytochem. 2019;67:663–81.
Lee BT, Ahmed FA, Hamm LL, Teran FJ, Chen CS, Liu Y, et al. Association of C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 with chronic kidney disease. BMC Nephrol. 2015;16:77.
Donate-Correa J, Martín-Núñez E, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. Inflammatory cytokines in diabetic nephropathy. J Diabetes Res. 2015;2015:948417.
Guo W, Feng JM, Yao L, Sun L, Zhu GQ. Transplantation of endothelial progenitor cells in treating rats with IgA nephropathy. BMC Nephrol. 2014;15:110.
Rao KB, Malathi N, Narashiman S, Rajan ST. Evaluation of myofibroblasts by expression of alpha smooth muscle actin: a marker in fibrosis, dysplasia and carcinoma. J Clin Diagn Res. 2014;8:ZC14–7.
Darby IA, Laverdet B, Bonté F, Desmoulière A. Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol. 2014;7:301–11.
Deng J, Kohda Y, Chiao H, Wang Y, Hu X, Hewitt SM, et al. Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int. 2001;60:2118–28.
Bussolati B, Bruno S, Grange C, Buttiglieri S, Deregibus MC, Cantino D, et al. Isolation of renal progenitor cells from adult human kidney. Am J Pathol. 2005;166:545–55.
Lee SJ, Wang HJ, Kim TH, Choi JS, Kulkarni G, Jackson JD, et al. In situ tissue regeneration of renal tissue induced by collagen hydrogel injection. Stem Cells Transl Med. 2018;7:241–50.
Li Y, Rodrigues J, Tomás H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chem Soc Rev. 2012;41:2193–221.
Yeo Y, Geng W, Ito T, Kohane DS, Burdick JA, Radisic M. Photocrosslinkable hydrogel for myocyte cell culture and injection. J Biomed Mater Res B Appl Biomater. 2007;81:312–22.
Acknowledgements
This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (HI14C3484), the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2021R1A2C2007189), the Korean Government (MSIT) (2018R1C1B5040264), and the Ministry of Trade, Industry, and Energy (R0005886).
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The animal studies were performed procedures following an animal protocol approved by the Yeungnam University Institutional Animal Care and Use Committee (IACUC, YUMC-AEC2016-032).
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Khunmanee, S., Chun, S.Y., Ha, YS. et al. Improvement of IgA Nephropathy and Kidney Regeneration by Functionalized Hyaluronic Acid and Gelatin Hydrogel. Tissue Eng Regen Med 19, 643–658 (2022). https://doi.org/10.1007/s13770-022-00442-8
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DOI: https://doi.org/10.1007/s13770-022-00442-8