Podoplanin-positive cell-derived small extracellular vesicles contribute to cardiac amyloidosis after myocardial infarction

Summary: Cardiac amyloidosis is a secondary phenomenon of an already pre-existing chronic condition. Whether cardiac amyloidosis represents one of the complications post myocardial infarction (MI) has yet to be fully understood. Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived serum amyloid A 3 (SAA3) monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from cardiac stromal cells (CSCs), which, in response to MI, activate the expression of a platelet aggregation-inducing type I transmembrane glycoprotein, Podoplanin (PDPN). CSCPDPN+-derived small extracellular vesicles (sEVs) are enriched in SAA3, and exosomal SAA3 engages with macrophage by Toll-like receptor 2, triggering overproduction with consequent impaired clearance and aggregation of SAA3 monomers into rigid fibers. SAA3 amyloid deposits reduce cardiac contractility and increase scar stiffness. Inhibition of SAA3 aggregation by retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils and improves heart function post MI

Non-coding RNAs in Cardiac Regeneration

Cardiovascular disease is a leading cause of death worldwide, and with the dramatically increasing numbers of heart failure patients in the next 10 years, mortality will only increase [1]. For patients with end-stage heart failure, heart transplantation is the sole option. Regrettably, the number of available donor hearts is drastically lower than the number of patients waiting for heart transplantation. Despite evidence of cardiomyocyte renewal in adult human hearts, regeneration of functional myocardium after injury can be neglected. The limited regenerative capacity due to inadequate proliferation of existing cardiomyocytes is insufficient to repopulate areas of lost myocardium [2]. As a solution, the hypothesis that adult stem cells could be employed to generate functional cardiomyocytes was proposed. One of the early studies that supported this hypothesis involved direct injection of hematopoietic c-kit-positive cells derived from bone marrow into the infarcted heart [3]. However, in sharp contrast, more recent evidence emerged demonstrating that these hematopoietic stem cells only differentiate into cells down the hematopoietic lineage rather than into cardiomyocytes [4, 5], and the focus shifted towards stem cells residing in the heart, called cardiac progenitor cells. These CPCs were extracted and injected into the myocardium to regenerate the heart [6]. In recent years, over 80 pre-clinical studies employing cardiac stem cells in vivo in large and small animals to evaluate the effect on functional parameters were systematically reviewed, identifying differences between large and small animals [7]. Despite the positive outcome of these stem cell therapies on functional parameters, c-kit-positive cardiac progenitor cells were shown to contribute minimally to the generation of functional cardiomyocytes [8, 9]. This heavily debated topic is summarized concisely by van Berlo and Molkentin [10]. Recently, single-cell sequencing and genetic lineage tracing of proliferative cells in the murine heart in both homeostatic and regenerating conditions did not yield a quiescent cardiac stem cell population or other cell types that support transdifferentiation into cardiomyocytes, nor did it support proliferation of cardiac myocytes [11, 12]. Now, the focus is shifting towards exploiting the limited regenerative capacity of the cardiomyocytes themselves, by re-activating proliferation of existing cardiomyocytes through dedifferentiation, reentry into the cell cycle, and cytokinesis. This process is the new focus of research to promote cardiac regeneration, and can be controlled on multiple levels, including cell-cycle manipulation, reprogramming, small molecules, extra-cellular matrix (ECM), proteins, and RNA regulation [13]