Abstract
Rapid vascularization is required for the regeneration of dental pulp due to the spatially restricted tooth environment. Extracellular vesicles (EVs) released from mesenchymal stromal cells show potent proangiogenic effects. Since EVs suffer from rapid clearance and low accumulation in target tissues, an injectable delivery system capable of maintaining a therapeutic dose of EVs over a longer period would be desirable. We fabricated an EV-fibrin gel composite as an in situ forming delivery system. EVs were isolated from dental pulp stem cells (DPSCs). Their effects on cell proliferation and migration were monitored in monolayers and hydrogels. Thereafter, endothelial cells and DPSCs were co-cultured in EV-fibrin gels and angiogenesis as well as collagen deposition were analyzed by two-photon laser microscopy. Our results showed that EVs enhanced cell growth and migration in 2D and 3D cultures. EV-fibrin gels facilitated vascular-like structure formation in less than seven days by increasing the release of VEGF. The EV-fibrin gel promoted the deposition of collagen I, III, and IV, and readily induced apoptosis during the initial stage of angiogenesis. In conclusion, we confirmed that EVs from DPSCs can promote angiogenesis in an injectable hydrogel in vitro, offering a novel and minimally invasive strategy for regenerative endodontic therapy.
Highlights
Dental pulp tissue can be damaged in the case of caries by the penetration of bacteria or by a dental trauma
We measured the level of other proangiogenic factors in the extracellular vesicles (EVs) lysate, revealing that FGFb and leptin were present at significantly higher levels than VEGF; TGFβ and EGF were present at similar levels to VEGF; TNFα and IGF1 were present at low levels; IL6 was not detected (Figure 4F)
EV-Loaded Fibrin Gels Accelerate the Rate of Apoptosis during Initial Angiogenesis
Summary
Dental pulp tissue can be damaged in the case of caries by the penetration of bacteria or by a dental trauma. The ability of MSC-derived EVs to carry therapeutically relevant molecules that stimulate angiogenesis and tissue repair was demonstrated by the dose-dependent enhancement of endothelial cell proliferation, migration, and tube formation. This was shown for dental pulp cell-derived exosomes that stimulated human umbilical vein endothelial cell (HUVECs) angiogenesis [7]. G20e2t0h, 2e1r, 4w22i6th the internalization assay, these results show that the EVs exerte5dofp1o7sitive effects on the growth of HUVECs in monolayer culture and on 3D co-cultured HUVECs and DPSCs in EV-loaded fibrin gels This effect lasted for seven days, suggesting that an effective dose was avagirloawblteh oinvheirbitthioenwafhteorle12ohb.seInrvthaetio3Dn pgeelrsi,owde. A similar trend of migration pinateE2hffDVwe-claaotTsnyaadodkwened3antDhsfiteboaagrglsisrensootahwgfyeeotsrlhus,w.ontThfidthHehiisUnmtheVtiffehgEeierCncatts3teliDiaronsnntcmaehlddiozeinfamsoottrialooasntyneacevxaereisncsosuafdalytasE,usytVrashe,y-etsa,srunebegdaurgetoteesnstudth3litneHDsgmsUcthohiVo-gacwEtruaaCltttnhuisoaerwnefft detadhcHstieisUvfEtoeaVVundEsncoCeedsxsewetawornataedsbsderDaepvPsdoaiSgusiClincatsiebivfidlineec. aBnottlhy difofevreerntthefrwomhoCleMob-streervaatetidonHpUerVioEdC. s (Figure 3D)
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