Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection

Bin Yu, Ha Won Kim, Min Gong, Jingcai Wang, Ronald W. Millard, Yigang Wang, Muhammad Ashraf, Meifeng Xu

Research output: Contribution to journalArticle

153 Citations (Scopus)

Abstract

Background: Exosomes play an important role in intercellular signaling and exert regulatory function by carrying bioactive molecules. This study investigated (1) the cardioprotective capabilities of exosomes derived from mesenchymal stem cells (MSCs) overexpressing GATA-4 (MSCGATA-4) and (2) its underlying regulatory mechanisms for expression of target proteins in recipient cells. Methods and results: Exosomes were isolated and purified from MSCGATA-4 (ExoGATA-4) and control MSCs (ExoNull). Cell injury was investigated in primary cultured rat neonatal cardiomyocytes (CM) and in the rat heart. Exosomes contributed to increased CM survival, reduced CM apoptosis, and preserved mitochondrial membrane potential in CM cultured under a hypoxic environment. Direct intramyocardial transplantation of exosomes at the border of an ischemic region following ligation of the left anterior descending coronary artery significantly restored cardiac contractile function and reduced infarct size. Real-time PCR revealed that several anti-apoptotic miRs were highly expressed in ExoGATA-4. Rapid internalization of ExoGATA-4 by CM was documented using time-lapse imaging. Subsequent expression of these miRs, particularly miR-19a was higher in CM and in the myocardium treated with ExoGATA-4 compared to those treatedwith ExoNull. The enhanced protective effects observed in CM were diminished by the inhibition of miR-19a. The expression level of PTEN, a predicted target of miR-19a, was reduced in CM treated with ExoGATA-4, which resulted in the activation of the Akt and ERK signaling pathways. Conclusions: ExoGATA-4 upon transplantation in the damaged tissue mediate protection by releasing multiple miRs responsible for activation of the cell survival signaling pathway.

Original languageEnglish (US)
Pages (from-to)349-360
Number of pages12
JournalInternational Journal of Cardiology
Volume182
Issue numberC
DOIs
StatePublished - Jan 1 2015

Fingerprint

Exosomes
MicroRNAs
Mesenchymal Stromal Cells
Cardiac Myocytes
Transplantation
Time-Lapse Imaging
MAP Kinase Signaling System
Mitochondrial Membrane Potential
Ligation
Real-Time Polymerase Chain Reaction
Cell Survival
Coronary Vessels
Myocardium
Apoptosis
Wounds and Injuries

Keywords

  • Bone marrow stem cells
  • Cardioprotection
  • Exosomes
  • GATA-4
  • MiR transfer
  • Target proteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. / Yu, Bin; Kim, Ha Won; Gong, Min; Wang, Jingcai; Millard, Ronald W.; Wang, Yigang; Ashraf, Muhammad; Xu, Meifeng.

In: International Journal of Cardiology, Vol. 182, No. C, 01.01.2015, p. 349-360.

Research output: Contribution to journalArticle

@article{8804b40fbac244a5b6f62a1151181741,
title = "Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection",
abstract = "Background: Exosomes play an important role in intercellular signaling and exert regulatory function by carrying bioactive molecules. This study investigated (1) the cardioprotective capabilities of exosomes derived from mesenchymal stem cells (MSCs) overexpressing GATA-4 (MSCGATA-4) and (2) its underlying regulatory mechanisms for expression of target proteins in recipient cells. Methods and results: Exosomes were isolated and purified from MSCGATA-4 (ExoGATA-4) and control MSCs (ExoNull). Cell injury was investigated in primary cultured rat neonatal cardiomyocytes (CM) and in the rat heart. Exosomes contributed to increased CM survival, reduced CM apoptosis, and preserved mitochondrial membrane potential in CM cultured under a hypoxic environment. Direct intramyocardial transplantation of exosomes at the border of an ischemic region following ligation of the left anterior descending coronary artery significantly restored cardiac contractile function and reduced infarct size. Real-time PCR revealed that several anti-apoptotic miRs were highly expressed in ExoGATA-4. Rapid internalization of ExoGATA-4 by CM was documented using time-lapse imaging. Subsequent expression of these miRs, particularly miR-19a was higher in CM and in the myocardium treated with ExoGATA-4 compared to those treatedwith ExoNull. The enhanced protective effects observed in CM were diminished by the inhibition of miR-19a. The expression level of PTEN, a predicted target of miR-19a, was reduced in CM treated with ExoGATA-4, which resulted in the activation of the Akt and ERK signaling pathways. Conclusions: ExoGATA-4 upon transplantation in the damaged tissue mediate protection by releasing multiple miRs responsible for activation of the cell survival signaling pathway.",
keywords = "Bone marrow stem cells, Cardioprotection, Exosomes, GATA-4, MiR transfer, Target proteins",
author = "Bin Yu and Kim, {Ha Won} and Min Gong and Jingcai Wang and Millard, {Ronald W.} and Yigang Wang and Muhammad Ashraf and Meifeng Xu",
year = "2015",
month = "1",
day = "1",
doi = "10.1016/j.ijcard.2014.12.043",
language = "English (US)",
volume = "182",
pages = "349--360",
journal = "International Journal of Cardiology",
issn = "0167-5273",
publisher = "Elsevier Ireland Ltd",
number = "C",

}

TY - JOUR

T1 - Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection

AU - Yu, Bin

AU - Kim, Ha Won

AU - Gong, Min

AU - Wang, Jingcai

AU - Millard, Ronald W.

AU - Wang, Yigang

AU - Ashraf, Muhammad

AU - Xu, Meifeng

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: Exosomes play an important role in intercellular signaling and exert regulatory function by carrying bioactive molecules. This study investigated (1) the cardioprotective capabilities of exosomes derived from mesenchymal stem cells (MSCs) overexpressing GATA-4 (MSCGATA-4) and (2) its underlying regulatory mechanisms for expression of target proteins in recipient cells. Methods and results: Exosomes were isolated and purified from MSCGATA-4 (ExoGATA-4) and control MSCs (ExoNull). Cell injury was investigated in primary cultured rat neonatal cardiomyocytes (CM) and in the rat heart. Exosomes contributed to increased CM survival, reduced CM apoptosis, and preserved mitochondrial membrane potential in CM cultured under a hypoxic environment. Direct intramyocardial transplantation of exosomes at the border of an ischemic region following ligation of the left anterior descending coronary artery significantly restored cardiac contractile function and reduced infarct size. Real-time PCR revealed that several anti-apoptotic miRs were highly expressed in ExoGATA-4. Rapid internalization of ExoGATA-4 by CM was documented using time-lapse imaging. Subsequent expression of these miRs, particularly miR-19a was higher in CM and in the myocardium treated with ExoGATA-4 compared to those treatedwith ExoNull. The enhanced protective effects observed in CM were diminished by the inhibition of miR-19a. The expression level of PTEN, a predicted target of miR-19a, was reduced in CM treated with ExoGATA-4, which resulted in the activation of the Akt and ERK signaling pathways. Conclusions: ExoGATA-4 upon transplantation in the damaged tissue mediate protection by releasing multiple miRs responsible for activation of the cell survival signaling pathway.

AB - Background: Exosomes play an important role in intercellular signaling and exert regulatory function by carrying bioactive molecules. This study investigated (1) the cardioprotective capabilities of exosomes derived from mesenchymal stem cells (MSCs) overexpressing GATA-4 (MSCGATA-4) and (2) its underlying regulatory mechanisms for expression of target proteins in recipient cells. Methods and results: Exosomes were isolated and purified from MSCGATA-4 (ExoGATA-4) and control MSCs (ExoNull). Cell injury was investigated in primary cultured rat neonatal cardiomyocytes (CM) and in the rat heart. Exosomes contributed to increased CM survival, reduced CM apoptosis, and preserved mitochondrial membrane potential in CM cultured under a hypoxic environment. Direct intramyocardial transplantation of exosomes at the border of an ischemic region following ligation of the left anterior descending coronary artery significantly restored cardiac contractile function and reduced infarct size. Real-time PCR revealed that several anti-apoptotic miRs were highly expressed in ExoGATA-4. Rapid internalization of ExoGATA-4 by CM was documented using time-lapse imaging. Subsequent expression of these miRs, particularly miR-19a was higher in CM and in the myocardium treated with ExoGATA-4 compared to those treatedwith ExoNull. The enhanced protective effects observed in CM were diminished by the inhibition of miR-19a. The expression level of PTEN, a predicted target of miR-19a, was reduced in CM treated with ExoGATA-4, which resulted in the activation of the Akt and ERK signaling pathways. Conclusions: ExoGATA-4 upon transplantation in the damaged tissue mediate protection by releasing multiple miRs responsible for activation of the cell survival signaling pathway.

KW - Bone marrow stem cells

KW - Cardioprotection

KW - Exosomes

KW - GATA-4

KW - MiR transfer

KW - Target proteins

UR - http://www.scopus.com/inward/record.url?scp=84947201437&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947201437&partnerID=8YFLogxK

U2 - 10.1016/j.ijcard.2014.12.043

DO - 10.1016/j.ijcard.2014.12.043

M3 - Article

C2 - 25590961

AN - SCOPUS:84947201437

VL - 182

SP - 349

EP - 360

JO - International Journal of Cardiology

JF - International Journal of Cardiology

SN - 0167-5273

IS - C

ER -