PDLSCs Regulate Angiogenesis of Periodontal Ligaments via VEGF Transferred by Exosomes in Periodontitis

Abstract

Abnormal angiogenesis is one of the significant features in periodontitis leading to progressive inflammation, but angiogenic changes of periodontal ligaments under inflammatory condition were rarely reported. Periodontal ligament stem cells (PDLSCs) were a kind of dental stem cells associated with vascularization. Here we investigated the alteration of angiogenesis of periodontal ligament in periodontitis, and revealed an exosome-mediated pathway to support the effect of PDLSCs on angiogenic improvement. Vascular specific marker CD31 and VEGFA were found to be highly expressed in periodontal ligaments of periodontitis. The VEGFA expression was up-regulated in inflamed PDLSCs compared to control, meanwhile the tube formation of HUVECs was improved when co-cultured with inflamed PDLSCs. Exosomes secretion of PDSLCs was augmented by inflammation, and promoted angiogenesis of HUVECs, whereas blocking secretion of exosomes led to degenerated angiogenesis of HUVECs. Exosome-trasferred VEGFA was proven to be the crucial communicator between PDLSCs and HUVECs. Inflammation inhibited miR-17-5p expression of PDLSCs and relieved its target VEGFA. However, overexpression of miR-17-5p blocked the pro-angiogenic ability of inflamed PDLSCs. In conclusion, the findings indicated that vascularization of periodontal ligaments was enhanced, and inflammatory micro-environment of periodontitis facilitated pro-angiogenesis of PDLSCs through regulating exosome-mediated transfer of VEGFA, which was targeted by miR-17-5p.

Autophagy and its significance in periodontal disease

“…Abnormal angiogenesis is a significant feature of periodontal inflammation 71 . Mesenchymal stem cells (MSCs), including PDLSCs, have been shown to promote angiogenesis, in which autophagy plays a role 72‐74 . The secretion of angiogenin (Ang) and basic fibroblast growth factor (bFGF), two important angiogenesis‐promoting cytokines, was upregulated under inflammatory conditions 68 .…”

The Case of Medication-Related Osteonecrosis of the Jaw Addressed from a Pathogenic Point of View. Innovative Therapeutic Strategies: Focus on the Most Recent Discoveries on Oral Mesenchymal Stem Cell-Derived Exosomes

“…DPSCs, PDLSCs, SHED, SCAP human ultracentrifugation [112,114,[116][117][118]124,125,128,[132][133][134]141] SMCs (maxilla), PCs rat ultracentrifugation [138] DPSCs human Oral mucosa MSCs human density gradient differential centrifugation [142] DPSCs: dental pulp stem cells; PDLSCs: periodontal ligament stem cells; SHEDs: stem cells from exfoliated deciduous teeth; GMSC: gingival mesenchymal stem cells; SMC: sinus mucosa-derived cells; PCs: mandibular periosteum-derived cells; SCAP: stem cells from apical papilla; N.A. : not available.…”

“…According to Zhang et al, inflammation was responsible for miR-17-5p down-regulation in PDLSCs which, in turn, accounted for increased expression of VEGFA in exosomes derived from inflamed PDLSCs. The exosomes-mediated transfer of VEGFA to endothelial cells finally contributed to the increased vascularization of periodontal ligaments in periodontitis ( Figure 4D) [128].…”

Emerging role of exosomes in craniofacial and dental applications

“…Angiogenesis, which provides nutrition and oxygen to the surrounding cells, is a vital step in bone healing. Exosomes derived from multiple types of cells, including the bone marrow-derived MSCs (BMSCs) 66 , 67 , ADSCs 68 - 70 , human placenta-derived MSCs (hP-MSCs) 71 , 72 , periodontal ligament stem cells (PDLSCs) 73 promote in vitro proliferation, migration, and tube formation of endothelial cells.…”

“…In vitro studies have shown that exosomes involved in inflammatory signal transfer and periodontitis progression, which may provide therapeutic targets for periodontal regeneration 76 , 90 , 91 . Royo et al demonstrated that exosomes derived from PDLSCs regulate angiogenesis via the exosome-mediated transfer of miR-17-5p-targeted VEGFA 73 . Additionally, SHEDs-derived exosomes enhance PDLSCs osteogenic differentiation partly due to the presence of Wnt3a and BMP2 in the exosomes.…”