Abstract 13877: Podoplanin Positive Cell-Derived Extracellulatr Vesicles as Novel Mediators of Cardiac Amyloidosis After Myocardial Infarction

Abstract

Amyloidosis represent a major long-term complication of myocardial infarction (MI);however, the exact mechanisms of post-MI cardiac amyloidosis are yet to be fullyunderstood. Onset of amyloid fibers deposition alongside with extra-cellular-matrix (ECM)proteins in the ischemic tissue exacerbates rigidity and stiffness of the scar hindering thecontractility of viable myocardium in the left ventricle. Amyloid proteins, at the site of injury, are released after inflammation mostly by activated immune cells and mesenchymalstomal cells. We have reported earlier that two days after MI, a cohort of mesenchymalstromal cells begin to de novo express Podoplanin (PDPN), a platelet aggregation-inducing type I transmembrane glycoprotein, as a sign of activation. PDPN acquisitionallows mesenchymal stromal cells to communicate with macrophages bearing PDPNreceptor, a C-type lectin-like receptor 2 (CLEC-2). Here we show that in addition to cell-to-cell contact, Podoplanin positive cells (PDPN+ cells) further activate macrophagesthrough their extracellular vesicles or exosomes. Specifically, PDPN+ cells derivedexosomes deliver Serum Amyloid A 3 (SAA3) protein that, after binding to Toll-likereceptor 2 (TRL2) on macrophages, triggers an overproduction of SAA3 in macrophages,with consequent impaired clearance of SAA3. Saturated lysosomes release SAA3protofilaments that are prone to misfold and aggregate as extracellular, insoluble, andrigid amyloid deposits leading to cardiac amyloidosis. We show that injection of exosomesfrom PDPN+ mesenchymal stromal cells induce infiltrating fibrosis, SAA3 deposition anddepressed cardiac function in healthy mouse hearts. Using SAA3 and TLR loss-of-function mouse models we show that SAA3 delivered by PDPN+ cell exosomes have alocal function in promoting post-MI amyloidosis. In vivo administration of newly developedD-peptide inhibits the aggregation of misfolded SAA3 with consequent scar stiffnessreduction and positive modulation of the ischemic heart function. In addition to providingnew mechanistic insights into post-MI amyloidosis, our findings suggest that SAA3 maybe an attractive target for effective scar reversal after ischemic injury.