RNF20-mediated transcriptional pausing and VEGFA splicing orchestrate vessel growth.

Signal-responsive gene expression is essential for vascular development, yet the mechanisms integrating signaling inputs with transcriptional activities are largely unknown. Here we show that RNF20, the primary E3 ubiquitin ligase for histone H2B, plays a multifaceted role in sprouting angiogenesis. RNF20 mediates RNA polymerase (Pol II) promoter-proximal pausing at genes highly paused in endothelial cells, involved in VEGFA signaling, stress response, cell cycle control and mRNA splicing.

Role of endothelial PDGFB in arterio-venous malformations pathogenesis.

Arterial-venous malformations (AVMs) are direct connections between arteries and veins without an intervening capillary bed. Either familial inherited or sporadically occurring, localized pericytes (PCs) drop is among the AVMs' hallmarks. Whether impaired PC coverage triggers AVMs or it is a secondary event is unclear.

SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations.

Vascular networks form, remodel, and mature under the influence of both fluid shear stress (FSS) and soluble factors. Physiological FSS promotes and maintains vascular stability via synergy with bone morphogenic proteins 9 and 10 (BMP9 and BMP10). Conversely, mutation of the BMP receptors activin-like kinase 1 (ALK1), endoglin (ENG), or the downstream effector, SMAD family member 4 (SMAD4) leads to hereditary hemorrhagic telangiectasia (HHT), characterized by fragile and leaky arterial-venous malformations (AVMs).

25-hydroxyvitamin D generates immunomodulatory plasticity in human periodontal ligament-derived mesenchymal stromal cells that is inflammatory context-dependent.

Introduction: Human periodontal ligament-derived mesenchymal stromal cells (hPDL-MSCs) exhibit a tight bi-directional interaction with CD4 T lymphocytes. The hPDL-MSCs' immunomodulatory abilities are drastically enhanced by pro-inflammatory cytokines via boosting the expression of various immunomediators. 25-hydroxyvitamin D (25(OH)D), the major metabolite of vitamin D3 in the blood, affects both hPDL-MSCs and CD4 T lymphocytes, but its influence on their interaction is unknown.

Effect of vitamin D on the osteogenic differentiation of human periodontal ligament stromal cells under inflammatory conditions.

Objectives: Vitamin D is known to activate osteogenic differentiation of human periodontal ligament stromal cells (hPDLSCs). Recently, inflammatory stimuli were shown to inhibit the transcriptional activity of hPDLSCs, but their effect on vitamin D -induced osteogenic differentiation is not known. The present study aimed to investigate whether the effects of 1,25-dihydroxvitamin D (1,25(OH) D ) and 25-hydroxvitamin D (25(OH)D ) on the osteogenic differentiation of hPDLSCs are also altered under inflammatory conditions.

Anti-apoptotic effects of human gingival mesenchymal stromal cells on polymorphonuclear leucocytes.

Objectives: Polymorphonuclear leucocytes (PMNs) constitute the first line of host defence and are crucial in maintaining periodontal health. Their survival and function are modulated by mesenchymal stromal cells (MSCs) from different origin. Gingival MSCs (GMSCs) play an important role in maintaining oral health and in the initial inflammatory response.

Continuing Effect of Cytokines and Toll-Like Receptor Agonists on Indoleamine-2,3-Dioxygenase-1 in Human Periodontal Ligament Stem/Stromal Cells.

Transplanted mesenchymal stem/stromal cells (MSCs) are a promising and innovative approach in regenerative medicine. Their regenerative potential is partly based upon their immunomodulatory activities. One of the most investigated immunomediators in MSCs, such as in periodontal ligament-derived MSCs (hPDLSCs), is indoleamine-2,3-dioxygenase-1 (IDO-1) which is upregulated by inflammatory stimuli, like cytokines.

Response of Human Mesenchymal Stromal Cells from Periodontal Tissue to LPS Depends on the Purity but Not on the LPS Source.

Human periodontal ligament stromal cells (hPDLSCs) and gingival mesenchymal stromal cells (hGMSCs) are resident mesenchymal stromal cells (MSCs) of the periodontal tissue. The lipopolysaccharide (LPS) from is structurally distinct from that of other Gram-negative bacteria, and earlier studies linked this structural difference to a distinct virulence activity and the ability to activate toll-like receptor 2 (TLR-2), besides TLR-4 as commonly occurring upon LPS challenge. Later studies, in contrast, argue that TLR-2 activation by LPS is due to lipoprotein contamination.

Transcriptional activity of vitamin D receptor in human periodontal ligament cells is diminished under inflammatory conditions.

Background: Although vitamin D deficiency is considered as a risk factor for periodontitis, supplementation during periodontal treatment has not been shown to be beneficial to date. Human periodontal ligament cells (hPDLCs) are regulated by vitamin D and play a fundamental role in periodontal tissue homeostasis and inflammatory response in periodontitis. The aim of this study is to investigate possible alterations of the vitamin D activity in hPDLCs under inflammatory conditions.

Cytokines Differently Define the Immunomodulation of Mesenchymal Stem Cells from the Periodontal Ligament.

Human periodontal ligament stem cells (hPDLSCs) play an important role in periodontal tissue homeostasis and regeneration. The function of these cells depends largely on their immunomodulatory ability, which is reciprocally regulated by immune cells via cytokines, particularly interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Different cytokines activate distinct signaling pathways and might differently affect immunomodulatory activities of hPDLSCs.

Effect of implant surface material and roughness to the susceptibility of primary gingival fibroblasts to inflammatory stimuli.

Objectives: The impact of the implant surface material and roughness on inflammatory processes in peri-implantitis is not entirely clear. Hence, we investigated how titanium and zirconia surfaces with different roughness influence the susceptibility of primary human gingival fibroblasts to different inflammatory stimuli.

Methods: Primary human gingival fibroblasts were isolated from 8 healthy individuals and cultured on following surfaces: smooth titanium machined surface (TiM), smooth zirconia machined surface (ZrM), moderately rough titanium surface (SLA), or moderately rough zirconia surface (ZLA).

Pleiotropic effects of vitamin D on CD4 T lymphocytes mediated by human periodontal ligament cells and inflammatory environment.

Aims: Both, vitamin D and human periodontal ligament cells (hPDLCs) possess immunosuppressive properties, but their combined effect on immune cells has never been investigated. Here, we analysed the impact of vitamin D on the immunosuppressive properties of hPDLCs towards CD4 T lymphocytes.

Material And Methods: Allogenic CD4 T lymphocytes were activated by phytohemagglutinin either in monoculture or co-culture with hPDLCs, in the presence or absence of IFN-γ and 1,25(OH) D .

1,25(OH)D Differently Affects Immunomodulatory Activities of Mesenchymal Stem Cells Depending on the Presence of TNF-α, IL-1β and IFN-γ.

Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)D on the immunomodulatory activities of hPDLSCs in the presence of different cytokines.

Soluble CD14 Enhances the Response of Periodontal Ligament Stem Cells to Toll-Like Receptor 2 Agonists.

Human periodontal ligament stem cells (hPDLSCs) do not express membrane-bound CD14, and their responsiveness to bacterial lipopolysaccharide (LPS) is drastically enhanced by soluble CD14 (sCD14), which is due to the facilitation of the interaction between LPS and Toll-like receptor- (TLR-) 4. Several studies also show that sCD14 enhances the responsiveness of different immune cells to TLR-2, but such effect in hPDLSCs has not been studied so far. In the present study, we investigated for the first time the potential effect of sCD14 on the hPDLSC response to two different TLR-2 agonists, .

Synergistic effects triggered by simultaneous Toll-like receptor-2 and -3 activation in human periodontal ligament stem cells.

Background: Although periodontitis is associated with disruption of the host-microbial homeostasis, viruses are currently discussed to influence disease progression. Viral pathogens are recognized by Toll-like receptor (TLR)-3, which engages a different signaling pathway than other TLRs. This study aimed to investigate the effect of TLR-3 agonist polyinosinic:polycytidylic acid (Poly I:C) on the expression of inflammatory markers and bone metabolism proteins by human periodontal ligament stem cells (hPDLSCs) compared with TLR-2 agonist Pam3CSK4, which mimics the effect of bacterial lipoproteins.