Kidney tissue regeneration using bioactive scaffolds incorporated with differentiating extracellular vesicles and intermediate mesoderm cells
Source abstract
Abstract
Abstract Background To overcome the limitations of current alternative therapies for chronic kidney disease (CKD), tissue engineering-mediated regeneration strategies have demonstrated the possibilities for complete kidney tissue regeneration. Given the challenges associated with the reproducibility of renal basal cells, the incorporation of intermediate mesoderm (IM) cells and bioactive materials to control bioactivities of cells with supported scaffolds should be considered as a viable approach to enable the regeneration of the complex kidney structure via renal differentiation. Methods We developed PMEZ scaffolds by combining crucial bioactive components, such as ricinoleic acid-grafted Mg(OH) 2 (M), extracellular matrix (E), and alpha lipoic acid-conjugated ZnO (Z) integrated into biodegradable porous PLGA (P) platform. Additionally, we utilized differentiating extracellular vesicles (dEV) isolated during intermediate mesoderm differentiation into kidney progenitor cells, and IM cells were serially incorporated to facilitate kidney tissue regeneration through their differentiation into kidney progenitor cells in the 3/4 nephrectomy mouse model. Results The use of differentiating extracellular vesicles facilitated IM differentiation into kidney progenitor cells without additional differentiation factors. This led to improvements in various regeneration-related bioactivities including tubule and podocyte regeneration, anti-fibrosis, angiogenesis, and anti-inflammation. Finally, implanting PMEZ/dEV/IM scaffolds in mouse injury model resulted in the restoration of kidney function. Conclusions Our study has demonstrated that utilizing biodegradable PLGA-based scaffolds, which include multipotent cells capable of differentiating into various kidney progenitor cells along with supporting components, can facilitate kidney tissue regeneration in the mouse model that simulates CKD through 3/4 nephrectomy. Graphical Abstract
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Renal and related cancers · Tissue Engineering and Regenerative Medicine · Genetic and Kidney Cyst Diseases
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam- si 13488, Gyeonggi-do, Republic of Korea.
Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon-si 16419, Gyeonggi-do, Republic of Korea.
Intelligent Precision of Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon-si 16419, Gyeonggi-do, Republic of Korea.
Joint Institute for Regenerative Medicine, Kyungpook National University, Jung-gu, Daegu 41944, Republic of Korea.
Bundang Medical Center, CHA Advanced Research Institute, CHA University, Sungnam- si 13488, Gyeonggi-do, Republic of Korea.
Department of Chemistry and Nanoscience, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea.
Department of Urology, School of Medicine, Kyungpook National University, Jung-gu, Daegu 41944, Republic of Korea.
Funding
Ministry of Science and ICT, South Korea
References (77)
Show source-provided references
1. Levey AS Coresh J. Chronic kidney disease. Lancet [Internet]. 2012;379:165–80. https://doi.org/10.1016/S0140-6736(11)60178-5.10.1016/S0140-6736(11)60178-5 ↗
2. 10.1634/stemcells.2006-018310.1634/stemcells.2006-0183 ↗
3. 10.1038/s41581-022-00542-710.1038/s41581-022-00542-7 ↗
4. 10.1016/j.celrep.2016.03.07610.1016/j.celrep.2016.03.076 ↗
5. Tan Z Shan J Rak-Raszewska A Vainio SJ. Embryonic stem cells derived kidney organoids as faithful models to target programmed nephrogenesis. Sci Rep. 2018;8.10.1038/s41598-018-34995-3 ↗
6. 10.1016/j.semcdb.2021.09.01710.1016/j.semcdb.2021.09.017 ↗
7. Khoshdel Rad N Aghdami N Moghadasali R. Cellular and molecular mechanisms of kidney development: From the embryo to the kidney organoid. Front. Cell Dev. Biol. Frontiers Media S.A.; 2020.10.3389/fcell.2020.00183 ↗
8. 10.1038/ncb289410.1038/ncb2894 ↗
9. 10.1038/ncb290410.1038/ncb2904 ↗
10. 10.1039/C9BM01103J10.1039/C9BM01103J ↗
11. 10.1002/adhm.20150016810.1002/adhm.201500168 ↗
12. Goodarzi H Hashemi-Najafabadi S Baheiraei N Bagheri F. Preparation and characterization of nanocomposite scaffolds (Collagen/β-TCP/SrO) for bone tissue engineering. Tissue Eng Regen Med [Internet]. 2019;16:237–51. https://doi.org/10.1007/s13770-019-00184-0.10.1007/s13770-019-00184-0 ↗
13. Grafahrend D Heffels KH Beer MV Gasteier P Möller M Boehm G et al. Degradable polyester scaffolds with controlled surface chemistry combining minimal protein adsorption with specific bioactivation. Nat Mater [Internet]. 2011;10:67–73. https://doi.org/10.1038/nmat2904.10.1038/nmat2904 ↗
14. Kim KJ Choi MS Shim JH Rhie JW. Bone morphogenetic protein 2-conjugated silica particles enhanced early osteogenic differentiation of adipose stem cells on the polycaprolactone scaffold. Tissue Eng Regen Med [Internet]. 2019;16:395–403. https://doi.org/10.1007/s13770-019-00195-x.10.1007/s13770-019-00195-x ↗
15. Salg GA Giese NA Schenk M Hüttner FJ Felix K Probst P et al. The emerging field of pancreatic tissue engineering: a systematic review and evidence map of scaffold materials and scaffolding techniques for insulin-secreting cells. J Tissue Eng. 2019;10.10.1177/2041731419884708 ↗
16. Lee HY Kim DS Hwang GY Lee JK Lee HL Jung JW et al. Multi-modulation of immune-inflammatory response using bioactive molecule-integrated PLGA composite for spinal fusion. Mater Today Bio [Internet]. 2023;19:100611. https://doi.org/10.1016/j.mtbio.2023.100611.10.1016/j.mtbio.2023.100611 ↗
17. 10.1002/advs.20220533610.1002/advs.202205336 ↗
18. Masud RA Islam MS Haque P Khan MNI Shahruzzaman M Khan M et al. Preparation of novel chitosan/poly (ethylene glycol)/ZnO bionanocomposite for wound healing application: Effect of gentamicin loading. Materialia. 2020;12.10.1016/j.mtla.2020.100785 ↗
19. 10.1002/bit.2717310.1002/bit.27173 ↗
20. Stratton S Shelke NB Hoshino K Rudraiah S Kumbar SG. Bioactive polymeric scaffolds for tissue engineering. Bioact Mater [Internet]. 2016;1:93–108. https://doi.org/10.1016/j.bioactmat.2016.11.001.10.1016/j.bioactmat.2016.11.001 ↗
21. 10.1016/j.bioactmat.2017.10.00110.1016/j.bioactmat.2017.10.001 ↗
22. Kim DH Kim DS Ha HJ Jung JW Baek SW Baek SH et al. Fat graft with allograft adipose matrix and magnesium hydroxide-incorporated PLGA microspheres for effective soft tissue reconstruction. Tissue Eng Regen Med [Internet]. 2022;19:553–63. https://doi.org/10.1007/s13770-021-00426-0.10.1007/s13770-021-00426-0 ↗
23. 10.1021/acsnano.8b0236510.1021/acsnano.8b02365 ↗
24. 10.1021/acscentsci.8b0081210.1021/acscentsci.8b00812 ↗
25. 10.1039/D0BM01934H10.1039/D0BM01934H ↗
26. Joshi R Han SB Cho WK Kim DH. The role of cellular traction forces in deciphering nuclear mechanics. Biomater Res [Internet]. 2022;26:1–17. https://doi.org/10.1186/s40824-022-00289-z.10.1186/s40824-022-00289-z ↗
27. Baek SW Kim DS Song DH Kim HB Lee S Kim JH et al. Reduced restenosis and enhanced re-endothelialization of functional biodegradable vascular scaffolds by everolimus and magnesium hydroxide. Biomater Res [Internet]. 2022;26:1–17. https://doi.org/10.1186/s40824-022-00334-x.10.1186/s40824-022-00334-x ↗
28. 10.3390/pharmaceutics1412266110.3390/pharmaceutics14122661 ↗
29. Yang T Fruergaard AS Winther AK Zelikin AN Chandrawati R. Zinc oxide particles catalytically generate nitric oxide from endogenous and exogenous prodrugs. Small. 2020;16.10.1002/smll.201906744 ↗
30. Liu S Zhang Y Li M Xiong L Zhang Z Yang X et al. Enzyme-mediated nitric oxide production in vasoactive erythrocyte membrane-enclosed coacervate protocells. Nat Chem [Internet]. 2020;12:1165–73. https://doi.org/10.1038/s41557-020-00585-y.10.1038/s41557-020-00585-y ↗
31. 10.1002/smll.20210576210.1002/smll.202105762 ↗
32. 10.1002/med.2173610.1002/med.21736 ↗
33. Baek SW Kim DS Lee JK Kim JH Lee S Park JM et al. Continuous NO dual-generation by ZnO nanoparticle conjugated with α-lipoic acid for functional biodegradable vascular stent. Chem Eng J [Internet]. 2023;470:144174. https://doi.org/10.1016/j.cej.2023.144174.10.1016/j.cej.2023.144174 ↗
34. 10.1039/D2BM01673G10.1039/D2BM01673G ↗
35. Jeong EK Jang HJ Kim SS Lee SY Oh MY Kim HJ et al. Protective Effect of Polydeoxyribonucleotide Against Renal Ischemia-Reperfusion Injury in Mice. Transplant Proc. 2016;48:1251–7.10.1016/j.transproceed.2016.01.028 ↗
36. 10.1089/scd.2008.009710.1089/scd.2008.0097 ↗
37. Kim JY Rhim WK Cha SG Woo J Lee JY Park CG et al. Bolstering the secretion and bioactivities of umbilical cord MSC-derived extracellular vesicles with 3D culture and priming in chemically defined media. Nano Converg [Internet]. 2022;9. https://doi.org/10.1186/s40580-022-00349-z.10.1186/s40580-022-00349-z ↗
38. Kim JY Rhim WK Woo J Cha SG Park CG Han DK. The upregulation of regenerative activity for Extracellular vesicles with melatonin modulation in chemically defined media. Int J Mol Sci. 2022;23.10.3390/ijms232315089 ↗
39. Théry C Witwer KW Aikawa E Alcaraz MJ Anderson JD Andriantsitohaina R et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7.
40. 10.1039/C7BM00479F10.1039/C7BM00479F ↗
41. 10.1038/ncb159610.1038/ncb1596 ↗
42. 10.3402/jev.v4.2706610.3402/jev.v4.27066 ↗
43. Lee JY Kim HS. Extracellular Vesicles in Regenerative Medicine: Potentials and Challenges. Tissue Eng Regen Med [Internet]. 2021;18:479–84. https://doi.org/10.1007/s13770-021-00365-w.10.1007/s13770-021-00365-w ↗
44. Yin H Li M Tian G Ma Y Ning C Yan Z et al. The role of extracellular vesicles in osteoarthritis treatment via microenvironment regulation. Biomater Res [Internet]. 2022;26:1–22. https://doi.org/10.1186/s40824-022-00300-7.10.1186/s40824-022-00300-7 ↗
45. Keshtkar S Azarpira N Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. 2018;1–9.10.1186/s13287-018-0791-7 ↗
46. Yea JH Yoon YM Lee JH Yun CW Lee SH. Exosomes isolated from melatonin-stimulated mesenchymal stem cells improve kidney function by regulating inflammation and fibrosis in a chronic Kidney Disease mouse model. J Tissue Eng. 2021;12.10.1177/20417314211059624 ↗
47. Yang T Zhao F Zhou L Liu J Xu L Dou Q et al. Therapeutic potential of adipose-derived mesenchymal stem cell exosomes in tissue-engineered bladders. J Tissue Eng. 2021;12.10.1177/20417314211001545 ↗
48. Hu S Wang Z Jin C Chen Q Fang Y Jin J et al. Human amniotic epithelial cell-derived extracellular vesicles provide an extracellular matrix-based microenvironment for corneal injury repair. J Tissue Eng. 2022;13.10.1177/20417314221122123 ↗
49. Ko K-W Park S-Y Lee EH Yoo Y-I Kim D-S Kim JY et al. Integrated Bioactive Scaffold with Polydeoxyribonucleotide and Stem-Cell-Derived Extracellular Vesicles for Kidney Regeneration. ACS Nano [Internet]. 2021;15:7575–85. https://doi.org/10.1021/acsnano.1c01098.10.1021/acsnano.1c01098 ↗
50. Najar M Krayem M Merimi M Burny A Meuleman N Bron D et al. Insights into inflammatory priming of mesenchymal stromal cells: functional biological impacts. Inflamm Res [Internet]. 2018;67:467–77. https://doi.org/10.1007/s00011-018-1131-1.10.1007/s00011-018-1131-1 ↗
51. Yang S Liu Q Chen S Zhang F Li Y Fan W et al. Extracellular vesicles delivering nuclear factor I/C for hard tissue engineering: treatment of apical periodontitis and dentin regeneration. J Tissue Eng. 2022;13.10.1177/20417314221084095 ↗
52. Thippabhotla S Zhong C He M. 3D cell culture stimulates the secretion of in vivo like extracellular vesicles. Sci Rep [Internet]. 2019;9:1–14. https://doi.org/10.1038/s41598-019-49671-3.10.1038/s41598-019-49671-3 ↗
53. 10.1111/nyas.1345110.1111/nyas.13451 ↗
54. 10.1186/s13287-018-1105-910.1186/s13287-018-1105-9 ↗
55. Staubach S Bauer FN Tertel T Börger V Stambouli O Salzig D et al. Scaled preparation of extracellular vesicles from conditioned media. Adv Drug Deliv Rev [Internet]. 2021;177:113940. https://doi.org/10.1016/j.addr.2021.113940.10.1016/j.addr.2021.113940 ↗
56. Kim JY Rhim WK Seo HJ Lee JY Park CG Han DK. Comparative Analysis of MSC-Derived Exosomes Depending on Cell Culture Media for Regenerative Bioactivity. Tissue Eng Regen Med [Internet]. 2021;18:355–67. https://doi.org/10.1007/s13770-021-00352-1.10.1007/s13770-021-00352-1 ↗
57. 10.1177/096368971879705310.1177/0963689718797053 ↗
58. 10.1021/acs.analchem.6b0239610.1021/acs.analchem.6b02396 ↗
59. 10.1039/D0BM01656J10.1039/D0BM01656J ↗
60. 10.1016/j.stem.2018.10.01010.1016/j.stem.2018.10.010 ↗
61. 10.1038/nprot.2008.4210.1038/nprot.2008.42 ↗
62. Pryzhkova MV Boers R Jordan PW. Modeling Human Gonad Development in Organoids. Tissue Eng Regen Med [Internet]. 2022;19:1185–206. https://doi.org/10.1007/s13770-022-00492-y.10.1007/s13770-022-00492-y ↗
63. Lam AQ Freedman BS Bonventre JV. Directed differentiation of pluripotent stem cells to kidney cells. Semin Nephrol [Internet]. 2014;34:445–61. https://doi.org/10.1016/j.semnephrol.2014.06.011.10.1016/j.semnephrol.2014.06.011 ↗
64. 10.1369/002215541985293210.1369/0022155419852932 ↗
65. 10.1146/annurev-physiol-022516-03422710.1146/annurev-physiol-022516-034227 ↗
66. 10.1002/stem.31010.1002/stem.310 ↗
67. Rovira J Diekmann F Campistol JM Ramírez-Bajo MJ. Therapeutic application of extracellular vesicles in acute and chronic renal injury. Nefrologia [Internet]. 2017;37:126–37. https://doi.org/10.1016/j.nefroe.2017.03.004.10.1016/j.nefroe.2017.03.004 ↗
68. 10.23876/j.krcp.19.05110.23876/j.krcp.19.051 ↗
69. 10.1038/s41581-022-00586-910.1038/s41581-022-00586-9 ↗
70. McLaughlin C Datta P Singh YP Lo A Horchler S Elcheva IA et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Therapeutic Use and in Bioengineering Applications. Cells. 2022.10.3390/cells11213366 ↗
71. Nassar W El-Ansary M Sabry D Mostafa MA Fayad T Kotb E et al. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res [Internet]. 2016;20:1–11. https://doi.org/10.1186/s40824-016-0068-0.10.1186/s40824-016-0068-0 ↗
72. Li H, Hohenstein P, Kuure S. Embryonic kidney development, stem cells and the origin of wilms Tumor. Genes (Basel). 2021;12:1–21.
73. Bussolati B Camussi G. Therapeutic use of human renal progenitor cells for kidney regeneration. Nat Rev Nephrol [Internet]. 2015;11:695–706. https://doi.org/10.1038/nrneph.2015.126.10.1038/nrneph.2015.126 ↗
74. 10.1681/ASN.201308083110.1681/ASN.2013080831 ↗
75. 10.1242/dev.03487610.1242/dev.034876 ↗
76. 10.1186/s40824-022-00252-y10.1186/s40824-022-00252-y ↗
77. 10.1046/j.1365-2672.2000.00791.x10.1046/j.1365-2672.2000.00791.x ↗