Network Analysis of Transcriptional Responses Induced by Mesenchymal Stem Cell Treatment of Experimental Sepsis
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3259279
- author
- 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
- organization
- publishing date
- 2012
- 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
- pmid:23083833
- 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
- 2016-04-01 11:10:35
- date last changed
- 2022-04-20 17:39:23
@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 <= 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}},
doi = {{10.1016/j.ajpath.2012.08.009}},
volume = {{181}},
year = {{2012}},
}