Podoplanin regulates the migration of mesenchymal stromal cells and their interaction with platelets

Abstract

Mesenchymal stromal cells (MSCs) upregulate podoplanin at sites of infection, chronic inflammation and cancer. Here, we investigated the functional consequences of podoplanin expression on the migratory potential of MSCs and their interactions with circulating platelets. Expression of podoplanin significantly enhanced the migration of MSCs compared to MSCs lacking podoplanin. Rac-1 inhibition altered the membrane localisation of podoplanin and in turn significantly reduced MSC migration. Blocking Rac-1 activity had no effect on the migration of MSCs lacking podoplanin, indicating that it was responsible for regulation of migration through podoplanin. When podoplanin-expressing MSCs were seeded on the basal surface of a porous filter, they were able to capture platelets perfused over the uncoated apical surface and induce platelet aggregation. Similar microthrombi were observed when endothelial cells (ECs) were co-cultured on the apical surface. Confocal imaging shows podoplanin-expressing MSCs extending processes into the EC layer, and these processes could interact with circulating platelets. In both models, platelet aggregation induced by podoplanin-expressing MSCs was inhibited by treatment with recombinant soluble C-type lectin-like receptor 2 (CLEC-2; encoded by the gene Clec1b). Thus, podoplanin may enhance the migratory capacity of tissue-resident MSCs and enable novel interactions with cells expressing CLEC-2.

Podoplanin is indispensable for cell motility and platelet-induced epithelial-to-mesenchymal transition-related gene expression in esophagus squamous carcinoma TE11A cells

“…PDPN has been previously found to bind to CLEC-2 on the platelet surface to induce platelet aggregation [23,35]. However, in this study, we found that TE11A cells completely deficient in PDPN were still able to induce platelet aggregation, with similar aggregation kinetics to the parental cells.…”

The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure

“…This could be due to a failure of infiltrating macrophages to egress from the inflamed liver in a timely fashion. Indeed there is a previously described role for the CLEC-2/podoplanin axis in facilitating the egress of other antigen presenting cells from lymphoid organs 44 and stromal cells from areas of inflammation 45 . Taken together these data suggest that activation of CLEC-2 signalling within platelets by macrophage expressed podoplanin within the acutely injured liver suppresses TNF-α release by those macrophages.…”

Cell motility and migration as determinants of stem cell efficacy

“…PDPN, a transmembrane mucin-like protein released within EVs [33] , plays a critical role in organ development, cell motility and migration [ 34 , 35 ]. On the other hand, PDPN is also associated with tumour cell invasiveness and migration including glioblastoma [ 36 , 37 ].…”

“…Origin-specific difference in PDPN expression has been reported for MSC isolated from the bone marrow or umbilical cord [39] . PDPN-dependent migration of MSC is suggested to be regulated by GTPase Rac-1 [35] which is also known to mediate tumour cell migration [40] . Our data reveal PDPN-dependent motility and migration of highly migrating subpopulations across two different classes of SC (MSC and NSC).…”