PMID- 24562010
OWN - NLM
STAT- MEDLINE
DCOM- 20150302
LR  - 20220409
IS  - 1873-734X (Electronic)
IS  - 1010-7940 (Linking)
VI  - 45
IP  - 6
DP  - 2014 Jun
TI  - Mechanisms of paracrine cardioprotection by cord blood mesenchymal stromal cells.
PG  - 983-92
LID - 10.1093/ejcts/ezt576 [doi]
AB  - OBJECTIVES: Among the mechanisms by which somatic stem cells may improve left 
      ventricular function in ischaemic heart disease are pro-survival stimuli mediated 
      by secreted factors. This phenomenon is frequently referred to, but remains 
      poorly understood. We therefore investigated the non-regenerative 
      cardioprotective effects of cord blood mesenchymal stromal cells (CBMSCs) in 
      vitro and sought to identify relevant intracellular signalling pathways. METHODS: 
      Conditioned medium from CBMSCs and fibroblasts was prepared, and secreted factors 
      were analysed by Luminex((R)) immunobead assay. Murine cardiomyocyte-derived HL-1 
      cells were subjected to simulated ischaemia by glucose and serum deprivation and 
      hypoxia in CBMSC-conditioned or cell-free control medium or in medium conditioned 
      by foreskin fibroblasts. The proportions of vital, apoptotic and necrotic cells 
      (poly-caspase activity, annexin V and ethidium homodimer-III staining) were 
      quantified using a high-content imaging system. Metabolic activity and 
      proliferation rate were determined via 
      3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium 
      and 5-bromo-2-deoxyuridine assays. Phosphorylation of Akt, 
      extracellular-signal-regulated kinase (ERK)1/2, signal transducer and activator 
      of transcription 3 (STAT3) and glycogen synthase kinase 3beta was determined by 
      western blot, and experiments were repeated in the presence of specific 
      small-molecule inhibitors (Wortmannin, UO126 and Stattic). RESULTS: CBMSC medium 
      reduced the proportion of dead HL-1 cardiomyocytes from 39 +/- 3 to 28 +/- 1% (P < 
      0.05) and the rate of late apoptotic cells to 68 +/- 2% of that in control medium 
      (P < 0.001). Metabolic activity was increased by 12 +/- 1% compared with control (P 
      < 0.05), while in fibroblast medium it was not (5 +/- 2%, P = 1). This was 
      associated with increased phosphorylation of Akt (2-fold, P < 0.05), ERK1/2 
      (3-fold, P < 0.01) and STAT3 (12-fold, P < 0.001). Combined blocking of the 
      phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt and mitogen-activated protein 
      kinase/ERK signalling abolished the protective CBMSC effect, while blocking the 
      pathways individually had no effect. Inhibition of STAT3 phosphorylation 
      drastically lowered HL-1 cell viability in control medium, but not in medium 
      conditioned by CBMSCs. CONCLUSIONS: The factors released by CBMSCs protect 
      cardiomyocyte-like HL-1 cells from simulated ischaemia more than those released 
      from fibroblasts. While CBMSC-triggered Akt and ERK1/2 activation provides 
      protection in a compensatory manner, STAT3 is crucial for cardiomyocyte survival 
      in ischaemia, but is not a key mediator of cytoprotective stem cell actions.
CI  - (c) The Author 2014. Published by Oxford University Press on behalf of the European 
      Association for Cardio-Thoracic Surgery. All rights reserved.
FAU - Bader, Andreas Matthaeus
AU  - Bader AM
AD  - Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
FAU - Brodarac, Andreja
AU  - Brodarac A
AD  - Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
FAU - Klose, Kristin
AU  - Klose K
AD  - Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
FAU - Bieback, Karen
AU  - Bieback K
AD  - Institute of Transfusion Medicine and Immunology, Mannheim, Germany.
FAU - Choi, Yeong-Hoon
AU  - Choi YH
AD  - Heart Center, University of Cologne, Cologne, Germany.
FAU - Kurtz, Andreas
AU  - Kurtz A
AD  - Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
FAU - Stamm, Christof
AU  - Stamm C
AD  - Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany 
      Deutsches Herzzentrum Berlin, Berlin, Germany stamm@dhzb.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140220
PL  - Germany
TA  - Eur J Cardiothorac Surg
JT  - European journal of cardio-thoracic surgery : official journal of the European 
      Association for Cardio-thoracic Surgery
JID - 8804069
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (STAT3 Transcription Factor)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
EIN - Eur J Cardiothorac Surg. 2014 Oct;46(4):759
MH  - Animals
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Culture Media, Conditioned/pharmacology
MH  - Fetal Blood/cytology
MH  - MAP Kinase Signaling System
MH  - Mesenchymal Stem Cells/*cytology/drug effects/*physiology
MH  - Mice
MH  - *Models, Cardiovascular
MH  - *Myocardial Ischemia
MH  - Myocytes, Cardiac/*cytology/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction/physiology
OTO - NOTNLM
OT  - Cardiomyocyte
OT  - Cell therapy
OT  - Cord blood
OT  - Ischaemia
OT  - Stem cell
EDAT- 2014/02/25 06:00
MHDA- 2015/03/03 06:00
CRDT- 2014/02/25 06:00
PHST- 2014/02/25 06:00 [entrez]
PHST- 2014/02/25 06:00 [pubmed]
PHST- 2015/03/03 06:00 [medline]
AID - ezt576 [pii]
AID - 10.1093/ejcts/ezt576 [doi]
PST - ppublish
SO  - Eur J Cardiothorac Surg. 2014 Jun;45(6):983-92. doi: 10.1093/ejcts/ezt576. Epub 
      2014 Feb 20.