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Nano Converg., Oct 26 2024, 11 (1) | https://doi.org/10.1186/s40580-024-00450-5 Multifunctional extracellular vesicles and edaravone-loaded scaffolds for kidney tissue regeneration by activating GDNF/RET pathway

Seung Yeon Lee^1†, Jeong Min Park^1†, Won‑Kyu Rhim^1†, Eun Hye Lee², Sang‑Hyuk Lee³, Jun Yong Kim¹, Seung‑Gyu Cha¹, Sun Hong Lee¹, Boram Kim¹, Dong‑Youn Hwang³, Seungsoo Rho⁴, Tae‑Keun Ahn⁵, Bum Soo Kim² and Dong Keun Han^1*

¹Department of Biomedical Science, CHA University, Seongnam, Gyeonggi‑Do 13488, Republic of Korea.

²Joint Institute for Regenerative Medicine, Kyungpook National University, Jung‑Gu, Daegu 41944, Republic of Korea.

³Department of Microbiology, School of Medicine, CHA University, Seongnam, Gyeonggi‑Do 13496, Republic of Korea.

⁴Department of Ophthalmology, CHA Bundang Medical Center, CHA University, 59 Yatap‑Ro, Bundang‑Gu, Seongnam, Gyeonggi‑Do 13496, Republic of Korea.

⁵Department of Orthopedic Surgery CHA Bundang Medical Center, CHA University, Seonnam, Gyeonggi‑Do 13496, Republic of Korea.

^†Seung Yeon Lee, Jeong Min Park and Won-Kyu Rhim have contributed equally to this work.

^*Correspondence: Dong Keun Han

Abstract

With the severity of chronic kidney disease worldwide, strategies to recover renal function via tissue regeneration provide alternatives to kidney replacement therapy. To exclude side effects from direct cell transplantation, extracellular vesicles (EVs) are great substitutes representing paracrine cell signaling. To build three-dimensional structures for implantation into the 5/6 nephrectomy model by incorporating bioactive materials, including multifunctional EVs (mEVs), porous PMEZE/mEV scaffolds were developed in combination with edaravone (EDV; E) and mEV based on PMEZ scaffolds with PLGA (P), MH-RA (M), ECM (E), ZnO-ALA (Z). The oxygen free radical scavenger EDV was incorporated to induce tubular regeneration. mEVs were engineered to serve regenerative activities with a combination of two EVs from SDF-1α overexpressed tonsil-derived mesenchymal stem cells (sEVs) and intermediate mesoderm (IM) cells during differentiation into kidney progenitor cells (dEVs). mEVs displayed beneficial effects on regeneration by facilitating migration and inducing differentiation of surrounding stem cells, and EDV improved kidney function by regulating the GDNF/RET pathway and their downstream genes. The promotion of MSC recruitment was confirmed with sEV particles number dependently, and the regulation of the GDNF/RET pathway by the effect of EDV and its enhanced effect by mEVs were elucidated using in vitro analysis. The regeneration of tubules was additionally demonstrated through the increased expression of aquaporin-1 (AQP-1) and cadherin-16 (CDH16) for proximal tubules, and calbindin and PAX2 for distal tubules in the renal defect model. With these, structural regeneration and functional recovery were achieved with kidney regeneration in the 5/6 nephrectomy mice model.

논문정보

형식Research article
게재일2024년 10월 (BRIC 등록일 2024-10-28)
연구진국내 연구진
분야 바이오·의료융합 > 바이오소재

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