Suppression of miR-181a attenuates H2O2-induced death of mesenchymal stem cells by maintaining hexokinase II expression.
BACKGROUND
Low survival rate of transplanted cells compromises the efficacy of cell therapy. Hexokinase II (HKII) is known to have anti-apoptotic activity through its interaction with mitochondria. The objective was to identify miRNAs targeting HKII and investigate whether miRNA-mediated modulation of HKII could improve the survival of mesenchymal stem cells (MSCs) exposed to H2O2. The expression of HKII in MSCs exposed to H2O2 was evaluated, and HKII-targeting miRNA was screened based on miRNA-target prediction databases. The effect of H2O2 on the expression of the selected HKII-targeting miRNA was examined and the effect of modulation of the selected HKII-targeting miRNA using anti-miRNA on H2O2-induced apoptosis of MSC was evaluated.


RESULTS
H2O2 (600 μM) induced cell death of MSCs and decreased mitochondrial HKII expression. We have identified miR-181a as a HKII-targeting miRNA and H2O2 increased the expression of miR-181a in MSCs. Delivery of anti-miR-181a, which neutralizes endogenous miR-181a, significantly attenuated H2O2-induced decrease of HKII expression and disruption of mitochondrial membrane potential, improving the survival of MSCs exposed to H2O2.


CONCLUSIONS
These findings suggest that H2O2-induced up-regulation of miR-181a contributes to the cell death of MSCs by down-regulating HKII. Neutralizing miR-181a can be an effective way to prime MSCs for transplantation into ischemic tissues.
Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 210-701, Republic of Korea. sam1017@ish.or.kr.
Seahyoung
S
Lee
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, 120-752, Republic of Korea. inayun88@yuhs.ac.
Ina
I
Yun
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, 120-752, Republic of Korea. ojham@yuhs.ac.
Onju
O
Ham
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, 120-752, Republic of Korea. sylee31@yuhs.ac.
Se-Yeon
SY
Lee
Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul, 120-752, Republic of Korea. cylee1@yuhs.ac.
Chang Yeon
CY
Lee
Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul, 120-752, Republic of Korea. yrjgmb@yuhs.ac.
Jun-Hee
JH
Park
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, 120-752, Republic of Korea. jylee12@yuhs.ac.
Jiyun
J
Lee
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, 120-752, Republic of Korea. shh17@yuhs.ac.
Hyang-Hee
HH
Seo
Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 210-701, Republic of Korea. ehchoi@ish.or.kr.
Eunhyun
E
Choi
Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 210-701, Republic of Korea. kchwang@cku.ac.kr.
Ki-Chul
KC
Hwang
D017209:Apoptosis; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D009361:Neoplasm Invasiveness; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism
C540193:MIrn181 microRNA, human; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D017382:Reactive Oxygen Species; C409766:SEMA3B protein, human; D039961:Semaphorins; D006861:Hydrogen Peroxide; D006593:Hexokinase