PMID- 22558198
OWN - NLM
STAT- MEDLINE
DCOM- 20120913
LR  - 20220318
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 4
DP  - 2012
TI  - Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and 
      have contrasting effects on chemotaxis and apoptosis.
PG  - e35685
LID - 10.1371/journal.pone.0035685 [doi]
LID - e35685
AB  - We have previously shown that mesenchymal stem cells (MSC) improve function upon 
      integration in ischemic myocardium. We examined whether specific cytokines and 
      growth factors produced by MSCs are able to affect angiogenesis, cellular 
      migration and apoptosis. Conditioned media (CM) was prepared by culturing MSC for 
      48 hours. CM displayed significantly elevated levels of VEGF, Monocyte 
      Chemoattractant Protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), 
      MIP-1beta and monokine induced by IFN-gamma (MIG) compared to control media. MSC 
      contained RNA for these factors as detected by RT-PCR. CM was able to induce 
      angiogenesis in canine vascular endothelial cells. MCP-1 and MIP-1alpha increased 
      cell migration of MSC while VEGF reduced it. H9c2 cells treated with CM under 
      hypoxic conditions for 24 hours displayed a 16% reduction in caspase-3 activity 
      compared to controls. PI 3-kinase gamma inhibitor had no effect on controls but 
      reversed the effect of CM on caspase-3 activity. MCP-1 alone mimicked the 
      protective effect of CM while the PI 3-Kgamma inhibitor did not reverse the effect of 
      MCP-1. CM reduced phospho-BAD (Ser112) and phospho-Akt (Ser473) while increasing 
      phospho-Akt (Thr308). MCP-1 reduced the level of phospho-Akt (Ser473) while 
      having no effect on the other two; the PI 3-Kgamma inhibitor did not alter the MCP-1 
      effect. ERK 1/2 phosphorylation was reduced in CM treated H9c2 cells, and 
      inhibition of ERK 1/2 reduced the phosphorylation of Akt (Ser473), Akt (Thr308) 
      and Bad (Ser112). In conclusion, MSC synthesize and secrete multiple paracrine 
      factors that are able to affect MSC migration, promote angiogenesis and reduce 
      apoptosis. While both MCP-1 and PI3-kinase are involved in the protective effect, 
      they are independent of each other. It is likely that multiple pro-survival 
      factors in addition to MCP-1 are secreted by MSC which act on divergent 
      intracellular signaling pathways.
FAU - Boomsma, Robert A
AU  - Boomsma RA
AD  - Department of Biology, Trinity Christian College, Palos Heights, Illinois, United 
      States of America.
FAU - Geenen, David L
AU  - Geenen DL
LA  - eng
GR  - R01 HL071046/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120425
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Cytokines)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspase 3/genetics/metabolism
MH  - Cell Differentiation/drug effects
MH  - Cell Survival/drug effects
MH  - Chemotaxis/drug effects
MH  - Culture Media, Conditioned/pharmacology
MH  - Cytokines/biosynthesis/metabolism/*pharmacology
MH  - Dogs
MH  - Endothelial Cells/cytology/drug effects/*metabolism
MH  - Gene Expression/*drug effects
MH  - Mesenchymal Stem Cells/cytology/*metabolism
MH  - Mice
MH  - Neovascularization, Physiologic/*drug effects
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Primary Cell Culture
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Signal Transduction/drug effects
PMC - PMC3338452
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/05/05 06:00
MHDA- 2012/09/14 06:00
PMCR- 2012/04/25
CRDT- 2012/05/05 06:00
PHST- 2011/09/08 00:00 [received]
PHST- 2012/03/22 00:00 [accepted]
PHST- 2012/05/05 06:00 [entrez]
PHST- 2012/05/05 06:00 [pubmed]
PHST- 2012/09/14 06:00 [medline]
PHST- 2012/04/25 00:00 [pmc-release]
AID - PONE-D-11-17622 [pii]
AID - 10.1371/journal.pone.0035685 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(4):e35685. doi: 10.1371/journal.pone.0035685. Epub 2012 Apr 25.