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Network Analysis of Transcriptional Responses Induced by Mesenchymal Stem Cell Treatment of Experimental Sepsis

dos Santos, Claudia C.; Murthy, Srinivas; Hu, Pingzhao; Shan, Yuexin; Haitsma, Jack J. LU ; Mei, Shirley H. J.; Stewart, Duncan J. and Liles, W. Conrad (2012) In American Journal of Pathology 181(5). p.1681-1692
Abstract
Although bone marrow derived mesenchymal stem cell (MSC) systemic administration reduces sepsis-associated inflammation, organ injury, and mortality in clinically relevant models of polymicrobial sepsis, the cellular and molecular mechanisms mediating beneficial effects are controversial. This study identifies the molecular mechanisms of MSC-conferred protection in sepsis by interrogating transcriptional responses of target organs to MSC therapy. Sepsis was induced in C57B1/6J mice by cecal ligation and puncture, followed 6 hours later by an i.v. injection of either MSCs or saline. Total RNA from lungs, hearts, kidneys, livers, and spleens harvested 28 hours after cecal ligation and puncture was hybridized to mouse expression bead arrays.... (More)
Although bone marrow derived mesenchymal stem cell (MSC) systemic administration reduces sepsis-associated inflammation, organ injury, and mortality in clinically relevant models of polymicrobial sepsis, the cellular and molecular mechanisms mediating beneficial effects are controversial. This study identifies the molecular mechanisms of MSC-conferred protection in sepsis by interrogating transcriptional responses of target organs to MSC therapy. Sepsis was induced in C57B1/6J mice by cecal ligation and puncture, followed 6 hours later by an i.v. injection of either MSCs or saline. Total RNA from lungs, hearts, kidneys, livers, and spleens harvested 28 hours after cecal ligation and puncture was hybridized to mouse expression bead arrays. Common transcriptional responses were analyzed using a network knowledge-based approach. A total of 4751 genes were significantly changed between placebo- and MSC-treated mice (adjusted P <= 0.05). Transcriptional responses identified three common effects of MSC administration in all five organs examined: i) attenuation of sepsis-induced mitochondrial-related functional derangement, ii down-regulation of endotoxin/Toll-like receptor innate immune proinflammatory transcriptional responses, and iii) coordinated expression of transcriptional programs implicated in the preservation of endothelial/vascular integrity. Transcriptomic analysis indicates that the protective effect of MSC therapy in sepsis is not limited to a single mediator or pathway but involves a range of complementary activities affecting biological networks playing critical roles in the control of host cell metabolism and inflammatory response. (Am J Pathol 2012, 181:1681-1692; http://dx.doi.org/10.1016/j.ajpath.2012.08.009) (Less)
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type
Contribution to journal
publication status
published
subject
in
American Journal of Pathology
volume
181
issue
5
pages
1681 - 1692
publisher
American Society for Investigative Pathology
external identifiers
  • wos:000310656800019
  • scopus:84868131407
ISSN
1525-2191
DOI
10.1016/j.ajpath.2012.08.009
language
English
LU publication?
yes
id
c1247cf4-713f-4818-8dbe-030d79de5ac0 (old id 3259279)
date added to LUP
2013-01-07 09:38:13
date last changed
2017-11-19 03:23:01
@article{c1247cf4-713f-4818-8dbe-030d79de5ac0,
  abstract     = {Although bone marrow derived mesenchymal stem cell (MSC) systemic administration reduces sepsis-associated inflammation, organ injury, and mortality in clinically relevant models of polymicrobial sepsis, the cellular and molecular mechanisms mediating beneficial effects are controversial. This study identifies the molecular mechanisms of MSC-conferred protection in sepsis by interrogating transcriptional responses of target organs to MSC therapy. Sepsis was induced in C57B1/6J mice by cecal ligation and puncture, followed 6 hours later by an i.v. injection of either MSCs or saline. Total RNA from lungs, hearts, kidneys, livers, and spleens harvested 28 hours after cecal ligation and puncture was hybridized to mouse expression bead arrays. Common transcriptional responses were analyzed using a network knowledge-based approach. A total of 4751 genes were significantly changed between placebo- and MSC-treated mice (adjusted P &lt;= 0.05). Transcriptional responses identified three common effects of MSC administration in all five organs examined: i) attenuation of sepsis-induced mitochondrial-related functional derangement, ii down-regulation of endotoxin/Toll-like receptor innate immune proinflammatory transcriptional responses, and iii) coordinated expression of transcriptional programs implicated in the preservation of endothelial/vascular integrity. Transcriptomic analysis indicates that the protective effect of MSC therapy in sepsis is not limited to a single mediator or pathway but involves a range of complementary activities affecting biological networks playing critical roles in the control of host cell metabolism and inflammatory response. (Am J Pathol 2012, 181:1681-1692; http://dx.doi.org/10.1016/j.ajpath.2012.08.009)},
  author       = {dos Santos, Claudia C. and Murthy, Srinivas and Hu, Pingzhao and Shan, Yuexin and Haitsma, Jack J. and Mei, Shirley H. J. and Stewart, Duncan J. and Liles, W. Conrad},
  issn         = {1525-2191},
  language     = {eng},
  number       = {5},
  pages        = {1681--1692},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {Network Analysis of Transcriptional Responses Induced by Mesenchymal Stem Cell Treatment of Experimental Sepsis},
  url          = {http://dx.doi.org/10.1016/j.ajpath.2012.08.009},
  volume       = {181},
  year         = {2012},
}