Abstract 13404: Lps Improves Msc-mediated Cardioprotection in a Mouse Model of Cardiac Ischemia/reperfusion Injury via Myd88 and Stat3 Signaling
Background: Bone marrow-derived mesenchymal cells (MSCs) improve cardiac function following ischemia/reperfusion injury, in part due to the release of paracrine factors such as VEGF, HGF and SDF-1. Toll-like receptor 4 (TLR4) is expressed in MSCs to regulate the expression of cytoprotective factors, cytokines, and chemokines. Upon stimulation by its ligand such as LPS, TLR4 activates two distinct signaling pathways that are either MyD88-dependent or MyD88-independent/TRIF-dependent. While it was reported previously that LPS treatment improved MSC-mediated cardioprotection, the mechanism underlying such improved effect remains unknown.
Methods and Results: To study a mechanism for LPS in MSC cardioprotective activity, both WT and MyD88-/- MSCs were treated with or without LPS (200 ng/ml) for 24 h. WT-MSCs, MyD88-/- MSCs, LPS-MSCs and LPS-MyD88-/- MSCs (1x10^5 each) were infused into the coronary circulation of isolated mouse hearts (Langendorff model) and then subjected to ischemia (25 min) and reperfusion (50 min). Saline served as a control. Both WT-MSCs and LPS-MSCs significantly increased post-ischemic recovery of myocardial function, as evidenced by improved Left Ventricular Developed Pressure (LVDP) and Ventricular Contractility Assessment (+/-dp/dt) during the reperfusion period (p<0.05), and LPS pre-treated MSCs conferred better cardiac function recovery than WT-MSCs (p<0.05). In contrast, although MyD88-/- MSCs alone demonstrated modest cardioprotection, LPS did not further improve this effect. Western blot and cytokine array assays showed that LPS increased p-STAT3 levels and the expression of VEGF in WT MSCs, but not MyD88-/- MSCs, and LPS-MSCs mediated cardioprotection was negated by STAT3 knockdown by siRNA.
Conclusions: This study demonstrates that LPS improves MSC-mediated cardioprotection via MyD88-dependent activation of STAT3.
Author Disclosures: B. Xu: None. Y. Liu: None. B. Li: None. Y. Wang: None.
- © 2014 by American Heart Association, Inc.