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

Abstract

At present, only a few reports have addressed the possible contribution of the lymphatic vascular system to the pathogenesis of systemic sclerosis (SSc). Based on the evidence that blood vascular endothelial cells can undertake the endothelial-to-myofibroblast transition (EndMT) contributing to SSc-related skin fibrosis, we herein investigated whether the lymphatic endothelium might represent an additional source of profibrotic myofibroblasts through a lymphatic EndMT (Ly-EndMT) process. Skin sections from patients with SSc and healthy donors were immunostained for the lymphatic endothelial cell-specific marker lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in combination with α-smooth muscle actin (α-SMA) as the main marker of myofibroblasts. Commercial human adult dermal lymphatic microvascular endothelial cells (HdLy-MVECs) were challenged with recombinant human transforming growth factor-β1 (TGFβ1) or serum from SSc patients and healthy donors. The expression of lymphatic endothelial cell/myofibroblast markers was measured by quantitative real-time PCR, Western blotting and immunofluorescence. Collagen gel contraction assay was performed to assess myofibroblast-like cell contractile ability. Lymphatic endothelial cells in intermediate stages of the Ly-EndMT process (i.e., coexpressing LYVE-1 and α-SMA) were found exclusively in the fibrotic skin of SSc patients. The culturing of HdLy-MVECs with SSc serum or profibrotic TGFβ1 led to the acquisition of a myofibroblast-like morphofunctional phenotype, as well as the downregulation of lymphatic endothelial cell-specific markers and the parallel upregulation of myofibroblast markers. In SSc, the Ly-EndMT might represent a previously overlooked pathogenetic process bridging peripheral microlymphatic dysfunction and skin fibrosis development.

Single-Cell RNA-Sequencing Analyses Identify APLNR, INS-IGF2, RGCC Genes May Be Involved in the Pathogenesis of Systemic Sclerosis Skin

“…45 Moreover, a recent viewpoint has proposed the potential emergence of lymphatic EndMT in the SSc skin, suggesting that this morpho-functional cell transition may serve as a pathogenetic connection between peripheral lymphatic network dysfunction or rarefaction in the primary phase of the disease and the progression of dermal fibrosis. 46 The sc-RNA-seq data indicates a clear connection between RGCC and EndMT in SSc skin, as evidenced by the Spearman analysis. This implies that RGCC may make contribution to the EndMT process of SSc skin, potentially impacting endothelial cells and lymphocytes.…”

“… 45 Moreover, a recent viewpoint has proposed the potential emergence of lymphatic EndMT in the SSc skin, suggesting that this morpho-functional cell transition may serve as a pathogenetic connection between peripheral lymphatic network dysfunction or rarefaction in the primary phase of the disease and the progression of dermal fibrosis. 46 …”

Involvement of Epithelial-Mesenchymal Transition (EMT) in Autoimmune Diseases

“…Micro-RNA 138 (MiR-138), a well-established repressor of EMT in several types of cancers [238], was found to be significantly decreased in the sera of patients with dcSSc and lcSSc compared to healthy controls, further pointing to the involvement of EMT in SSc pathophysiology [239]. In addition, the presence of an EMT-like process arising in endothelial cells, which is also referred to as endoMT, has also consistently been described in skin tissues taken from SSc patients [240][241][242][243]. Immunohistochemical analysis of skin biopsies from SSc showed significant upregulation of α-SMA, HIF-1α and VEGF-α compared with healthy controls.…”

“…Lymphatic endothelial cells were also linked with endoMT during histological analyses of skin sections from patients with SSc hybrid cells coexpressing lymphatic vessel endothelial hyaluronan receptor-1 LYVE-1, a specific marker of lymphatic endothelial cells, and α-SMA was found exclusively in the fibrotic skin of SSc patients. The culturing of HdLy-MVECs with SSc serum or profibrotic TGFβ1 led to the acquisition of a myofibroblast-like morphofunctional phenotype, as well as the downregulation of lymphatic endothelial cell-specific markers and the parallel upregulation of myofibroblast markers [242]. The distribution of OSM receptor β (OSMRβ) was significantly increased in dermal EC and in fibroblasts of SSc patients compared to controls.…”

The Role of TLR7 and TLR9 in the Pathogenesis of Systemic Sclerosis

“…During fibrosis in SSc, myofibroblasts are the key executors of fibrosis, and the increased expression of α-SMA is key evidence of fibroblast-to-myofibroblast transformations [ 45 ]. Myofibroblasts produce large amounts of collagen and other components of the extracellular matrix.…”