Exosomes derived from 3D-cultured MSCs improve therapeutic effects in periodontitis and experimental colitis and restore the Th17 cell/Treg balance in inflamed periodontium

Although mesenchymal stem cell-derived exosomes(MSC-exos)have been shown to have therapeutic effects in experimental periodontitis,their drawbacks,such as low yield and limited efficacy,have hampered their clinical application.These drawbacks can be largely reduced by replacing the traditional 2D culture system with a 3D system.However,the potential function of MSC-exos produced by 3D culture(3D-exos)in periodontitis remains elusive.This study showed that compared with MSC-exos generated via 2D culture(2D-exos),3D-exos showed enhanced anti-inflammatory effects in a ligature-induced model of periodontitis by restoring the reactive T helper 17(Th17)cell/Treg balance in inflamed periodontal tissues.Mechanistically,3D-exos exhibited greater enrichment of miR-1246,which can suppress the expression of Nfat5,a key factor that mediates Th17 cell polarization in a sequence-dependent manner.Furthermore,we found that recovery of the Th17 cell/Treg balance in the inflamed periodontium by the local injection of 3D-exos attenuated experimental colitis.Our study not only showed that by restoring the Th17 cell/Treg balance through the miR-1246/Nfat5 axis,the 3D culture system improved the function of MSC-exos in the treatment of periodontitis,but also it provided a basis for treating inflammatory bowel disease(IBD)by restoring immune responses in the inflamed periodontium.

Restoring periodontal tissue homoeostasis prevents cognitive decline by reducing the number of Serpina3nhigh astrocytes in the hippocampus

Cognitive decline has been linked to periodontitis through an undetermined pathophysiological mechanism.This study aimed to explore the mechanism underlying periodontitis-related cognitive decline and identify therapeutic strategies for this condition.Using single-nucleus RNA sequencing we found that changes in astrocyte number,gene expression,and cell‒cell communication were associated with cognitive decline in mice with periodontitis.In addition,activation of the NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome was observed to decrease the phagocytic capability of macrophages and reprogram macrophages to a more proinflammatory state in the gingiva,thus aggravating periodontitis.To further investigate this finding,lipid-based nanoparticles carrying NLRP3 siRNA(NPsiNLRP3)were used to inhibit overactivation of the NLRP3 inflammasome in gingival macrophages,restoring the oral microbiome and reducing periodontal inflammation.Furthermore,gingival injection of NPsiNLRP3 reduced the number of Serpina3nhigh astrocytes in the hippocampus and prevented cognitive decline.This study provides a functional basis for the mechanism by which the destruction of periodontal tissues can worsen cognitive decline and identifies nanoparticle-mediated restoration of gingival macrophage function as a novel treatment for periodontitis-related cognitive decline.

Exploration of the shared gene signatures and molecular mechanisms between periodontitis and inflammatory bowel disease:evidence from transcriptome data

Background:Periodontitis disease(PD)is associated with a systemic disorder of inflammatory bowel disease(IBD).The immune response is the common feature of the two conditions,but the more precise mechanisms remain unclear.Methods:Differential expressed genes(DEGs)analysis and weighted gene co-expression network analysis(WGCNA)were performed on PD and Crohn’s disease(CD)data sets to identify crosstalk genes linking the two diseases.The proportions of infiltrating immune cells were calculated by using Single-sample Gene Set Enrichment Analysis.In addition,a data set of isolated neutrophils from the circulation was performed via WGCNA to obtain PD-related key modules.Then,single-cell gene set enrichment scores were computed for the key module and grouped neutrophils according to score order in the IBD scRNA-seq data set.Single-cell gene enrichment analysis was used to further explore the biological process of the neutrophils.Results:A total of 13 crosstalk genes(IL1B,CSF3,CXCL1,CXCL6,FPR1,FCGR3B,SELE,MMP7,PROK2,SRGN,FCN1,TDO2 and CYP24A1)were identified via DEGs analysis and WGCNA by combining PD and CD data sets.The enrichment analysis showed that these genes were involved in interleukin-10 signaling and inflammatory response.The immune infiltration analysis showed a significant difference in the proportion of neutrophils in PD and CD compared with healthy patients.Neutrophils were scored based on the expression of a periodontitis-related gene set in the scRNA-seq data set of IBD.The enrichment analysis demonstrated that inflammatory response,TNFa signaling via NF-jB and interferon-gamma response were upregulated in the high-score group,which expressed more pro-inflammatory cytokines and chemokines compared with the low-score group.Conclusions:This study reveals a previously unrecognized mechanism linking periodontitis and IBD through crosstalk genes and neutrophils,which provides a theoretical framework for future research.