Role of Podoplanin-Positive Cells in Cardiac Fibrosis and Angiogenesis After Ischemia

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.

Full spectrum flow cytometry reveals mesenchymal heterogeneity in first trimester placentae and phenotypic convergence in culture, providing insight into the origins of placental mesenchymal stromal cells

“…Our understanding of mesenchymal heterogeneity is expanding exponentially, and advances in single-cell technologies have uncovered a wide spectrum of mesenchymal and endothelial phenotypes with specific functions and spatial distributions ( Suryawanshi et al, 2018 ; Takeda et al, 2019 ; Vijay et al, 2019 ). Mesenchymal heterogeneity can be used to spatially localise cells, identify cells involved in morphogenesis, angiogenesis or quiescence, and characterise inflammatory, anti-inflammatory, or invasive phenotypes ( Cimini and Kishore, 2021 ; Mezawa et al, 2019 ; Mezheyeuski et al, 2020 ; Nazari et al, 2016 ; Quintanilla et al, 2019 ). Dramatic advances in flow cytometry over the past few decades have enabled the simultaneous quantification of upwards of 30 antigens, allowing detection of in depth cell heterogeneity.…”

Lymphatic Endothelial-to-Myofibroblast Transition: A Potential New Mechanism Underlying Skin Fibrosis in Systemic Sclerosis

“…It is well established that lymphatic ECs are defined by the expression of typical markers, such as Prox1, LYVE-1, Flt4, and PDPN [21][22][23]. However, it is important to consider that even profibrotic α-SMA + fibroblasts have been demonstrated to express PDPN in a variety of disorders, including SSc-related cutaneous fibrosis and cardiac fibrosis [25,27], and that PDPN can be considered not only a reliable myofibroblast marker [24], but also a marker of aggressiveness in tumors, as this transmembrane glycoprotein promotes cancer cell migration and invasion, and is highly expressed in cancer-associated fibroblasts [26,28,29]. On this basis, we indeed considered the combination of PDPN and α-SMA markers unsuitable to search for Ly-EndMT in fibrotic skin sections, and thus chose LYVE-1 as the lymphatic EC-specific marker.…”

“…Lymphatic ECs can be distinguished from blood vascular ECs by the expression of distinctive markers, such as podoplanin (PDPN), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), vascular endothelial growth factor receptor-3 (also known as Flt4), as well as the nuclear factor prospero-related homeobox protein 1 (Prox1), which is a main regulator of lymphatic vessel development [21][22][23]. Of note, activated profibrotic fibroblasts/myofibroblasts observed in a variety of disorders, including SSc-related cutaneous fibrosis, have been shown to express PDPN [24][25][26][27][28][29]. Furthermore, a significant reduction in the number of lymphatic microvessels correlating with the progression of tissue fibrosis has been described in skin lesions of SSc patients [19].…”

Soluble podoplanin as a biomarker in diffuse‑type gastric cancer

“…Liu et al (17) also demonstrated that high PDPN expression in tissues reduces the sensitivity to adjuvant chemotherapy and correlates with poor prognosis of patients with gastric cancer. PDPN is a mucin-like transmembrane glycoprotein that is widely used as a marker for the lymphatic endothelium (18). PDPN expression in cancer cells has been reported in various tumor types, including brain tumors, esophageal squamous cell carcinoma, angiosarcoma, mesothelioma, squamous cell carcinoma of the lung and cervical carcinoma (19,20).…”