Abstract
New insights into the cellular and extra-cellular composition of scar tissue after myocardial infarction (MI) have been identified. Recently, a heterogeneous podoplanin-expressing cell population has been associated with fibrogenic and inflammatory responses and lymphatic vessel growth during scar formation. Podoplanin is a mucin-like transmembrane glycoprotein that plays an important role in heart development, cell motility, tumorigenesis, and metastasis. In the adult mouse heart, podoplanin is expressed only by cardiac lymphatic endothelial cells; after MI, it is acquired with an unexpected heterogeneity by PDGFRα-, PDGFRβ-, and CD34-positive cells. Podoplanin may therefore represent a sign of activation of a cohort of progenitor cells during different phases of post-ischemic myocardial wound repair. Podoplanin binds to C-type lectin-like receptor 2 (CLEC-2) which is exclusively expressed by platelets and a variety of immune cells. CLEC-2 is upregulated in CD11bhigh cells, including monocytes and macrophages, following inflammatory stimuli. We recently published that inhibition of the interaction between podoplanin-expressing cells and podoplanin-binding cells using podoplanin-neutralizing antibodies reduces but does not fully suppress inflammation post-MI while improving heart function and scar composition after ischemic injury. These data support an emerging and alternative mechanism of interactome in the heart that, when neutralized, leads to altered inflammatory response and preservation of cardiac function and structure. The overarching objective of this review is to assimilate and discuss the available evidence on the functional role of podoplanin-positive cells on cardiac fibrosis and remodeling. A detailed characterization of cell-to-cell interactions and paracrine signals between podoplanin-expressing cells and the other type of cells that compose the heart tissue is needed to open a new line of investigation extending beyond the known function of these cells. This review attempts to discuss the role and biology of podoplanin-positive cells in the context of cardiac injury, repair, and remodeling.
Highlights
New discoveries during the last decades have challenged the existing scientific dogmas and provided new conceptual developments in a number of scientific topics
Podoplanin is not expressed physiologically in the heart except in lymphatic endothelial cells and pericardial area, which means that probably it can be acquired over time by pericytes, mesenchymal stem cells (MSCs), and telocytes that reside in the heart and that are already positive for PDGFRβ, PDGFRα, and CD34
In order to solve this mystery, lineage tracing is needed to understand if these determined categories of cells are the ones that acquire this glycoprotein, and, if they do, what the major signal that contributes to the podoplanin expression is
Summary
New discoveries during the last decades have challenged the existing scientific dogmas and provided new conceptual developments in a number of scientific topics. In line with the growing knowledge on the postMI cardiac responses, it is imperative to further detail the cellular composition and evolution of heart tissue after injury In this regard, we (Cimini et al, 2017) characterized for the first time the presence of cells positive for a mucin-like transmembrane glycoprotein called podoplanin in the injured heart. The importance of de novo podoplanin expression comes from the fact that this glycoprotein is the only known ligand of C-type lectin-like receptor 2 (CLEC-2), highly expressed in platelets, activated monocytes, macrophages, and lymphocytes, and CLEC-2 signaling cascade contributes to the pro-inflammatory lineage of the immune cells (Table 1). Within the four different types of podoplanin coexpressing cells in injured heart described above, each specific group can be analyzed separately, PDGFRα-, PDGFRβ, CD34-positive cells and lymphatic endothelial cells have been collectively described to take part in regeneration, fibrosis, and inflammatory processes of the same pathologies. The binding between podoplanin and CLEC-2 following activation of CLEC-2
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