TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection

Yue Wang, Aaron M. Abarbanell, Jeremy L. Herrmann, Brent R. Weil, Mariuxi C. Manukyan, Jeffrey A. Poynter, Daniel R. Meldrum

Research output: Contribution to journalArticle

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Abstract

Background: Bone marrow-derived mesenchymal stem cells (MSC) improve myocardial recovery after ischemia/reperfusion (I/R) injury. These effects are mediated in part by the paracrine secretion of angiogenic and tissue growth-promoting factors. Toll-like receptor 4 (TLR4) is expressed by MSC and induces apoptosis and inhibits proliferation in neuronal progenitors as well as many other cell types. It is unknown whether knock-out (KO) of TLR4 will change the paracrine properties of MSC and in turn improve MSC-associated myocardial protection. Methodology/Principal Findings: This study explored the effect of MSC TLR4 on the secretion of angiogenic factors and chemokines in vitro by using ELISA and cytokine array assays and investigated the role of TLR4 on MSC-mediated myocardial recovery after I/R injury in an isolated rat heart model. We observed that MSC isolated from TLR4 KO mice exhibited a greater degree of cardioprotection in a rat model of myocardial I/R injury. This enhanced protection was associated with increased angiogenic factor production, proliferation and differentiation. TLR4-dificiency was also associated with decreased phosphorylation of PI-3K and AKT, but increased activation of STAT3. siRNA targeting of STAT3 resulted in attenuation of the enhanced cardioprotection of TLR4-deficient MSC. Conclusions/Significance: This study indicates that TLR4 exerts deleterious effects on MSC-derived cardioprotection following I/R by a STAT3 inhibitory mechanism.

Original languageEnglish
Article numbere14206
JournalPLoS One
Volume5
Issue number12
DOIs
StatePublished - 2010

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Toll-Like Receptor 4
Stem cells
Mesenchymal Stromal Cells
stem cells
Chemical activation
ischemia
Reperfusion Injury
Angiogenesis Inducing Agents
Rats
secretion
Myocardial Reperfusion Injury
Toll-like receptor 4
Recovery
Phosphorylation
phosphatidylinositol 3-kinase
production economics
chemokines
myocardial ischemia
small interfering RNA
Phosphatidylinositol 3-Kinases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wang, Y., Abarbanell, A. M., Herrmann, J. L., Weil, B. R., Manukyan, M. C., Poynter, J. A., & Meldrum, D. R. (2010). TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection. PLoS One, 5(12), [e14206]. https://doi.org/10.1371/journal.pone.0014206

TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection. / Wang, Yue; Abarbanell, Aaron M.; Herrmann, Jeremy L.; Weil, Brent R.; Manukyan, Mariuxi C.; Poynter, Jeffrey A.; Meldrum, Daniel R.

In: PLoS One, Vol. 5, No. 12, e14206, 2010.

Research output: Contribution to journalArticle

Wang, Yue ; Abarbanell, Aaron M. ; Herrmann, Jeremy L. ; Weil, Brent R. ; Manukyan, Mariuxi C. ; Poynter, Jeffrey A. ; Meldrum, Daniel R. / TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection. In: PLoS One. 2010 ; Vol. 5, No. 12.
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