Abstract
BackgroundBone 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 FindingsThis 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/SignificanceThis study indicates that TLR4 exerts deleterious effects on MSC-derived cardioprotection following I/R by a STAT3 inhibitory mechanism.
Highlights
Accumulating evidence indicates that mesenchymal stem cells (MSC) mediate their beneficial effects at least in part through the production of cytoprotective paracrine factors that reduce inflammation, decrease apoptosis and improve myocardial function [1,2,3,4,5, 6,7,8,9]
It is not known whether Toll-like receptor 4 (TLR4) regulates the activation of intracellular kinases such as STAT3, MAPK, PI-3K and AKT, whose activity has been shown to modulate the release of cytoprotective paracrine factors from MSC [16,27,28]
We hypothesized that TLR4-knockout (TLR4KO) MSC would confer a greater degree of cardioprotection against acute I/R by increasing angiogenic and tissue growthpromoting factor secretion, and that the protective effects of TLR4KO MSC would be associated with differential activation of the PI-3K, AKT, MAPK or STAT3 signaling pathways
Summary
Accumulating evidence indicates that MSC mediate their beneficial effects at least in part through the production of cytoprotective paracrine factors that reduce inflammation, decrease apoptosis and improve myocardial function [1,2,3,4,5, 6,7,8,9]. It is well established that MSC exert a protective role in hearts following acute ischemia and reperfusion (I/R) injury [3,5,15,17,26], it is unknown whether knock-out of TLR4 will increase MSC-mediated cardioprotection It is unclear if TLR4 regulates the paracrine properties of MSC. 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
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