title: let-7b suppresses apoptosis and autophagy of human mesenchymal stem cells transplanted into ischemia/reperfusion injured heart 7by targeting caspase-3.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) have therapeutic potential for the repair of myocardial injury. The efficacy of MSC therapy for myocardial regeneration mainly depends on the survival of cells after transplantation into the infarcted heart. In the transplanted regions, reactive oxygen species (ROS) can cause cell death, and this process depends on caspase activation and autophagosome formation.
  
  
  METHODS
  A Software TargetScan was utilized to search for microRNAs (miRNAs) that target caspase-3 mRNA. Six candidate miRNAs including let-7b were selected and transfected into human MSCs in vitro. Expression of MEK-EKR signal pathways and autophagy-related genes were detected. Using ischemia/reperfusion model (I/R), the effect of MSCs enriched with let-7b was determined after transplantation into infarcted heart area. Miller catheter was used to evaluate cardiac function.
  
  
  RESULTS
  Here, we report that let-7b targets caspase-3 to regulate apoptosis and autophagy in MSCs exposed to ROS. Let-7b-transfected MSCs (let-7b-MSCs) showed high expression of survival-related proteins, including p-MEK, p-ERK and Bcl-2, leading to a decrease in Annexin V/PI- and TUNEL-positive cells under ROS-rich conditions. Moreover, autophagy-related genes, including Atg5, Atg7, Atg12 and beclin-1, were significantly downregulated in let-7b-MSCs. Using a rat model of acute myocardial infarction, we found that intramyocardial injection of let-7b-MSCs markedly enhanced left ventricular (LV) function and microvessel density, in accordance with a reduced infarct size and the expression of caspase-3.
  
  
  CONCLUSIONS
  Taken together, these data indicate that let-7b may protect MSCs implanted into infarcted myocardium from apoptosis and autophagy by directly targeting caspase-3 signaling.
authors: Catholic Kwandong University International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea. onju1336@gmail.com.
authors: Onju
authors: O
authors: Ham
authors: Catholic Kwandong University International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea. seyeonlee31@gmail.com.
authors: Se-Yeon
authors: SY
authors: Lee
authors: Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, 120-752, Republic of Korea. cylee083@gmail.com.
authors: Chang Youn
authors: CY
authors: Lee
authors: Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, 120-752, Republic of Korea. yrjgmb@ish.or.kr.
authors: Jun-Hee
authors: JH
authors: Park
authors: Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, Republic of Korea. jylee12@yuhs.ac.
authors: Jiyun
authors: J
authors: Lee
authors: Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, Republic of Korea. shh17@yuhs.ac.
authors: Hyang-Hee
authors: HH
authors: Seo
authors: Catholic Kwandong University International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea. mjcha@ish.or.kr.|Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, 210-701, Republic of Korea. mjcha@ish.or.kr.
authors: Min-Ji
authors: MJ
authors: Cha
authors: Catholic Kwandong University International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea. ehchoi@ish.or.kr.|Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, 210-701, Republic of Korea. ehchoi@ish.or.kr.
authors: Eunhyun
authors: E
authors: Choi
authors: Catholic Kwandong University International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea. kimsoonhag@cku.ac.kr.|Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, 210-701, Republic of Korea. kimsoonhag@cku.ac.kr.
authors: Soonhag
authors: S
authors: Kim
authors: Catholic Kwandong University International St. Mary's Hospital, Incheon Metropolitan City, 404-834, Republic of Korea. kchwang@cku.ac.kr.|Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, 210-701, Republic of Korea. kchwang@cku.ac.kr.
authors: Ki-Chul
authors: KC
authors: Hwang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D035683:MicroRNAs; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D006861:Hydrogen Peroxide; D053148:Caspase 3