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Kidney Mesenchymal Stem Cell-derived Extracellular Vesicles Engineered to Express Erythropoietin Improve Renal Anemia in Mice with Chronic Kidney Disease

Authors
 Hoon Young Choi  ;  Tae Yeon Kim  ;  Mirae Lee  ;  Soo Hyun Kim  ;  Jong Hyun Jhee  ;  Yong Kyu Lee  ;  Hyung Jong Kim  ;  Hyeong Cheon Park 
Citation
 STEM CELL REVIEWS AND REPORTS, Vol.18(3) : 980-992, 2022-03 
Journal Title
STEM CELL REVIEWS AND REPORTS
ISSN
 2629-3269 
Issue Date
2022-03
MeSH
Anemia* / therapy ; Animals ; Creatinine ; Erythropoietin* / genetics ; Erythropoietin* / pharmacology ; Extracellular Vesicles* ; Female ; Humans ; Kidney / physiology ; Male ; Mesenchymal Stem Cells* ; Mice ; RNA, Messenger / genetics ; Renal Insufficiency, Chronic* / therapy
Keywords
Chronic kidney disease ; Erythropoietin ; Extracellular vesicles ; Kidney mesenchymal stem cells ; Renal anemia ; mRNA transfer
Abstract
Extracellular vesicles (EVs) shed from kidney mesenchymal stem cells (KMSCs) show protective effects against acute kidney injury and progressive kidney fibrosis via mRNA transfer. Previous studies report improvement of renal anemia following administration of genetically modified MSCs or peritoneal mesothelial cells that secrete erythropoietin (EPO). Here, we determined whether EPO-secreting KMSC-derived EVs (EPO(+)-EVs) can improve renal anemia in mouse models of chronic kidney disease (CKD). The mouse CKD and renal anemia model was induced by electrocoagulation of the right renal cortex and sequential left nephrectomy. At six weeks post-nephrectomy, we observed significantly lower hemoglobin (10.4 ± 0.2 vs. 13.2 ± 0.2 g/dL) and significantly higher blood urea nitrogen and serum creatinine levels in CKD mice relative to controls (60.5 ± 0.5 and 0.37 ± 0.09 mg/dL vs. 19.9 ± 0.5 and 0.12 ± 0.02 mg/dL, respectively). Genetically engineered EPO(+)-KMSCs secreted 71 IU/mL EPO/106 cells/24 h in vitro, and EPO(+)-EVs isolated by differential ultracentrifugation expressed EPO mRNA and horizontally transferred EPO mRNA into target cells in vitro and in vivo. Furthermore, at two weeks post-injection of EPO(+)-KMSCs or EPO(+)-EVs into CKD mice with renal anemia, we observed significant increases in hemoglobin levels (11.7 ± 0.2 and 11.5 ± 0.2 vs. 10.1 ± 0.2 g/dL, respectively) and significantly lower serum creatinine levels at eight weeks in comparison to mice receiving vehicle control (0.30 ± 0.00 and 0.23 ± 0.03 vs. 0.43 ± 0.06 mg/dL, respectively). These results demonstrate that intraperitoneal administration of EPO(+)-EVs significantly increased hemoglobin levels and renal function in CKD mice, suggesting the efficacy of these genetically engineered EVs as a promising novel strategy for the treatment of renal anemia.
Full Text
https://link.springer.com/article/10.1007/s12015-021-10141-x
DOI
10.1007/s12015-021-10141-x
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Park, Hyeong Cheon(박형천) ORCID logo https://orcid.org/0000-0002-1550-0812
Jhee, Jong Hyun(지종현)
Choi, Hoon Young(최훈영) ORCID logo https://orcid.org/0000-0002-4245-0339
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/189374
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