Activated Platelets Interfere with Recruitment of Mesenchymal Stem Cells to Apoptotic Cardiac Cells via High Mobility Group Box 1/Toll-like Receptor 4-mediated Down-regulation of Hepatocyte Growth Factor Receptor MET

Abstract

Background: Mesenchymal stem cells (MSC) contribute to cardiac repair after myocardial injury. Underlying molecular mechanisms remain unexplored. Results: Activated platelets inhibit recruitment of MSC to apoptotic cardiac myocytes and fibroblasts via HMGB1/TLR-4-mediated down-regulation of HGF receptor MET. Conclusion:We identify a novel mechanism by which platelets impair MSC migration to damaged cardiac cells. Significance: The cross-talk between platelets and MSC might be critical for myocardial repair.

Platelet-derived high-mobility group box 1 promotes recruitment and suppresses apoptosis of monocytes

“…We detected significant amounts of HMGB1 in CM derived from CRP/ADP-activated platelets with ELISA (p<0.02 for either combination) (Fig. 1B), indicating HMGB1 release by activated platelets, which is in accordance with recently published data [6–7]. The HMGB1 receptors RAGE, TLR2, and TLR4 were expressed on all monocyte preparations, as evaluated by flow cytometry (data not shown).…”

“…In another study, we have shown that platelet-derived HMGB1 inhibits recruitment of regenerative mesenchymal stem cells to apoptotic tissue cells [7]. Thus, the release of HMGB1 from activated platelets favors thrombosis and inflammation and suppresses mechanisms that potentially promote tissue repair and regeneration, which we have recently validated for necrotic cell-derived HMGB1 [14].…”

“…Platelets express high mobility group box 1 (HMGB1) [5–7], a highly conserved, non-histone, architectural DNA-binding protein that is typically abundant in the nucleus of mammalian cells [8]. HMGB1 may act as a damage-associated molecular pattern molecule (DAMP) [9] which initiates immune responses through recruitment/activation of monocytes/macrophages and dendritic cells [10–11] and downregulation of apoptosis of eosinophils, neutrophils, and other cells [12–13].…”

Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

“…Consistent with earlier reports, HMGB-1 was rarely detected in the plasma and was mainly an intracellular protein [103]. However, thrombin, collagen, C-reactive protein, or adenosine diphosphate induced translocation of HMGB-1 from the cytoplasm to the supernatant in platelets [104][105][106]. Interestingly, thrombin or collagen did not change the exosome secretion of purified platelets.…”

Organ-specific migration of mesenchymal stromal cells: Who, when, where and why?

“…Administration of a CRCR4 blocking antibody attenuated this enhancement suggesting that the CXCR4-CXCL12 axis may play an important role in MSC homing to the infarcted myocardium [101]. A possible explanation of the impaired migration comes from an in vitro study from Vogel et al in which they found that activated platelets inhibit recruitment of MSC to apoptotic cardiac myocytes and fibroblasts [102].…”