Similar articles

Abstract: periodontitis is a complex chronic inflammatory disease. The invasion of pathogens induces the inflammatory microenvironment in periodontitis. Cell behavior changes in response to changes in the microenvironment, which in turn alters the local inflammatory microenvironment of the periodontium through factors secreted by cells. It has been confirmed that periodontal ligament stem cells (PDLSCs) are vital in the development of periodontal disease. Moreover, PDLSCs are the most effective cell type to be used for periodontium regeneration. This review focuses on changes in PDLSCs, their basic biological behavior, osteogenic differentiation, and drug effects caused by the inflammatory microenvironment, to provide a better understanding of the influence of these factors on periodontal tissue homeostasis. In addition, we discuss the underlying mechanism in detail behind the reciprocal responses of PDLSCs that affect the microenvironment.

牙周膜干细胞与炎症微环境相互作用的主要生物学机制概述

[1]AnY, LiuWJ, XueP, et al., 2016. Increased autophagy is required to protect periodontal ligament stem cells from apoptosis in inflammatory microenvironment. J Clin Periodontol, 43(7):618-625.

[2]AroraP, LiW, HuangXB, et al., 2022. Metabolic reconfiguration activates stemness and immunomodulation of PDLSCs. Int J Mol Sci, 23(7):4038.

[3]ArthurJSC, LeySC, 2013. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol, 13(9):679-692.

[4]AshourL, Al HabashnehRA, Al-MrahelhMM, et al., 2020. The modulation of mature dendritic cells from patients with type 1 diabetes using human periodontal ligament stem cells. An in-vitro study. J Diabetes Metab Disord, 19(2):1037-1044.

[5]BakshD, BolandGM, TuanRS, 2007. Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation. J Cell Biochem, 101(5):1109-1124.

[6]ChenFM, GaoLN, TianBM, et al., 2016. Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial. Stem Cell Res Ther, 7:33.

[7]ChenMX, ZhongYJ, DongQQ, et al., 2021. Global, regional, and national burden of severe periodontitis, 1990‍‒2019: an analysis of the global burden of disease study 2019. J Clin Periodontol, 48(9):1165-1188.

[8]ChenMY, LinXB, ZhangL, et al., 2022. Effects of nuclear factor-‍κB signaling pathway on periodontal ligament stem cells under lipopolysaccharide-induced inflammation. Bioengineered, 13(3):7951-7961.

[9]ChewJRJ, ChuahSJ, TeoKYW, et al., 2019. Mesenchymal stem cell exosomes enhance periodontal ligament cell functions and promote periodontal regeneration. Acta Biomater, 89:252-264.

[10]DaluiskiA, EngstrandT, BahamondeME, et al., 2001. Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet, 27(1):84-88.

[11]DengJW, LuCT, ZhaoQT, et al., 2022. The Th17/Treg cell balance: crosstalk among the immune system, bone and microbes in periodontitis. J Periodontal Res, 57(2):‍246-255.

[12]DongJC, ShuR, 2022. The effect of inflammation on proliferation and osteogenic differentiation of periodontal ligament cells. Shanghai J Stomatol, 31(3):‍243-247 (in Chinese).

[13]DuanY, AnW, WuHM, et al., 2019. Salvianolic acid C attenuates LPS-induced inflammation and apoptosis in human periodontal ligament stem cells via Toll-like receptors 4 (TLR4)/nuclear factor kappa B (NF-‍κB) pathway. Med Sci Monit, 25:9499-9508.

[14]EijkenM, MeijerIMJ, WestbroekI, et al., 2008. Wnt signaling acts and is regulated in a human osteoblast differentiation dependent manner. J Cell Biochem, 104(2):568-579.

[15]El-SayedKMF, ElahmadyM, AdawiZ, et al., 2019. The periodontal stem/progenitor cell inflammatory-regenerative cross talk: a new perspective. J Periodontal Res, 54(2):81-94.

[16]El-SayedKMF, BittnerA, SchlichtK, et al., 2021. Ascorbic acid/retinol and/or inflammatory stimuli’s effect on proliferation/differentiation properties and transcriptomics of gingival stem/progenitor cells. Cells, 10(12):3310.

[17]EzhilarasanD, VargheseSS, 2022. Porphyromonas gingivalis and dental stem cells crosstalk amplify inflammation and bone loss in the periodontitis niche. J Cell Physiol, 237(10):3768-3777.

[18]FairleyM, UnruhDK, DonovanA, et al., 2013. Synthesis and characterization of homo- and heteronuclear molecular Al³⁺ and Th⁴⁺ species chelated by the ethylenediaminetetraacetate (edta) ligand. Dalton Trans, 42(37):13706-13714.

[19]FitriAR, PavasantP, ChamniS, et al., 2018. Asiaticoside induces osteogenic differentiation of human periodontal ligament cells through the Wnt pathway. J Periodontol, 89(5):596-605.

[20]FuZY, WangXS, LiB, et al., 2021. Fraxinellone alleviates inflammation and promotes osteogenic differentiation in lipopolysaccharide-stimulated periodontal ligament stem cells by regulating the bone morphogenetic protein 2/Smad pathway. Arch Oral Biol, 121:104927.

[21]González-OsunaL, Sierra-CristanchoA, CafferataEA, et al., 2022. Senescent CD4⁺CD28^- T lymphocytes as a potential driver of Th17/Treg imbalance and alveolar bone resorption during periodontitis. Int J Mol Sci, 23(5):2543.

[22]GuoJC, RenRY, SunK, et al., 2020. PERK controls bone homeostasis through the regulation of osteoclast differentiation and function. Cell Death Dis, 11(10):847.

[23]GuoSJ, KangJ, JiBH, et al., 2017. Periodontal-derived mesenchymal cell sheets promote periodontal regeneration in inflammatory microenvironment. Tissue Eng Part A, 23(13-14):585-596.

[24]HuangDH, LeiJ, LiXR, et al., 2022. Erythropoietin activates autophagy to regulate apoptosis and angiogenesis of periodontal ligament stem cells via the Akt/ERK1/2/BAD signaling pathway under inflammatory microenvironment. Stem Cells Int, 2022:9806887.

[25]HuangF, DingJ, ZhangMY, et al., 2017. The effects of lipopolysaccharide on the proliferation and inflammatory cytokine expression in human periodontal ligament stem cells. Chin J Conservative Dent, 27(2):86-88, 110 (in Chinese). https://doi.‍org/10.15956/j.‍cnki.‍chin.‍j.‍conserv.dent.2017.02.005

[26]HwangJW, ParkWJ, HanY, 2021. Asarylaldehyde enhances osteogenic differentiation of human periodontal ligament stem cells through the ERK/p38 MAPK signaling pathway. Biochem Biophys Res Commun, 545:27-32.

[27]IshitaniT, KishidaS, Hyodo-MiuraJ, et al., 2003. The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca²⁺ pathway to antagonize Wnt/β‍-catenin signaling. Mol Cell Biol, 23(1):131-139.

[28]JiangN, HeDQ, MaYS, et al., 2021. Force-induced autophagy in periodontal ligament stem cells modulates M1 macrophage polarization via AKT signaling. Front Cell Dev Biol, 9:666631.

[29]KangH, LeeMJ, ParkSJ, et al., 2018. Lipopolysaccharide-preconditioned periodontal ligament stem cells induce M1 polarization of macrophages through extracellular vesicles. Int J Mol Sci, 19(12):3843.

[30]KongXW, YeRD, LiuWJ, et al., 2015. Wnt/β‍-catenin signaling pathway mediates the impaired osteogenic differentiation of periodontal ligament stem cells in inflammatory microenvironment. Oral Biomed, 6(3):129-136 (in Chinese).

[31]KongXW, ChenB, ChengYC, et al., 2018. The biological characteristics of periodontal ligament stem cells in inflammatory microenvironment. Oral Biomed, 9(3):‍143-147 (in Chinese).

[32]KukoljT, TrivanovićD, DjordjevićIO, et al., 2018. Lipopolysaccharide can modify differentiation and immunomodulatory potential of periodontal ligament stem cells via ERK1,2 signaling. J Cell Physiol, 233(1):447-462.

[33]LeiXX, WangC, ZhaoX, 2021. The effect of BMPs-ERK5 signaling pathway on the osteogenic differentiation of periodontal ligament stem cells under inflammatory microenvironment. J Tissue Eng Reconstr Surg, 17(1):‍30-36 (in Chinese).

[34]LiCX, XiaoF, WenYS, et al., 2022. Krüppel-like factor 5-mediated Sirtuin6 promotes osteogenic differentiation and inhibits inflammatory injury of lipopolysaccharide-induced periodontal membrane stem cells by inhibiting nuclear factor kappa-B pathway. Bioengineered, 13(3):6966-6977.

[35]LiDY, WuMH, 2021. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther, 6:291.

[36]LiLY, LiuWJ, WangH, et al., 2018. Mutual inhibition between HDAC9 and miR-17 regulates osteogenesis of human periodontal ligament stem cells in inflammatory conditions. Cell Death Dis, 9(5):480.

[37]LiangQY, DuLQ, ZhangR, et al., 2021. Stromal cell-derived factor-1/Exendin-4 cotherapy facilitates the proliferation, migration and osteogenic differentiation of human periodontal ligament stem cells in vitro and promotes periodontal bone regeneration in vivo. Cell Prolif, 54(3):e12997.

[38]LinJY, HuangJC, ZhangZQ, et al., 2022. Periodontal ligament cells under mechanical force regulate local immune homeostasis by modulating Th17/Treg cell differentiation. Clin Oral Investig, 26(4):3747-3764.

[39]LinL, LiS, HuS, et al., 2023. UCHL1 impairs periodontal ligament stem cell osteogenesis in periodontitis. J Dent Res, 102(1):61-71.

[40]LingL, NurcombeV, CoolSM, 2009. Wnt signaling controls the fate of mesenchymal stem cells. Gene, 433(1-2):‍1-7.

[41]LiuHH, ZhengJW, ZhengTJ, et al., 2019. Exendin-4 regulates Wnt and NF-‍κB signaling in lipopolysaccharide-induced human periodontal ligament stem cells to promote osteogenic differentiation. Int Immunopharmacol, 75:105801.

[42]LiuJN, WangH, ZhangLD, et al., 2022. Periodontal ligament stem cells promote polarization of M2 macrophages. J Leukoc Biol, 111(6):1185-1197.

[43]LiuJY, ChenB, BaoJ, et al., 2019. Macrophage polarization in periodontal ligament stem cells enhanced periodontal regeneration. Stem Cell Res Ther, 10:320.

[44]LiuN, LiH, ZhangY, et al., 2015. Effects of Wnt/Ca²⁺ signaling pathway on osteogenic differentiation of human periodontal ligament stem cells in inflammatory microenvironment. Chin J Geriatr Dent, 13(5):257-262 (in Chinese).

[45]LiuN, ShiHG, ZhangW, et al., 2016. The crosstalk between canonical and noncanonical Wnt signaling pathway in osteoblast differentiation of periodontal ligament stem cells in inflammatory microenvironments. Chin J Stomatol, 51(11):673-679 (in Chinese).

[46]LiuN, LiY, WangYY, et al., 2021. The effects of co-culture of periodontal ligament stem cells and CD3⁺ T cells on Wnt/β-catenin signaling pathway in inflammatory microenvironments. Chin J Geriatr Dent, 19(2):70-76 (in Chinese).

[47]LiuOS, XuJJ, DingG, et al., 2013. Periodontal ligament stem cells regulate B lymphocyte function via programmed cell death protein 1. Stem Cells, 31(7):1371-1382.

[48]LiuW, LiuY, GuoT, et al., 2013. TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments. Cell Death Dis, 4(3):e539.

[49]LiuWJ, KonermannA, GuoT, et al., 2014. Canonical Wnt signaling differently modulates osteogenic differentiation of mesenchymal stem cells derived from bone marrow and from periodontal ligament under inflammatory conditions. Biochim Biophys Acta Gen Subj, 1840(3):‍1125-1134.

[50]LiuX, NiuY, XieW, et al., 2019. Tanshinone IIA promotes osteogenic differentiation of human periodontal ligament stem cells via ERK1/2-dependent Runx2 induction. Am J Transl Res, 11(1):340-350.

[51]LiuY, WangL, KikuiriT, et al., 2011. Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-‍γ and TNF-‍α. Nat Med, 17(12):1594-1601.

[52]LuoH, GaoHL, LiuF, et al., 2017. Regulation of Runx2 by microRNA-9 and microRNA-10 modulates the osteogenic differentiation of mesenchymal stem cells. Int J Mol Med, 39(4):1046-1052.

[53]MaY, LiSH, DingXX, et al., 2018. Effects of tumor necrosis factor-α on osteogenic differentiation and Notch signaling pathway in human periodontal ligament stem cells. West China J Stomatol, 36(2):184-189 (in Chinese).

[54]MaoCY, WangYG, ZhangX, et al., 2016. Double-edged-sword effect of IL-1β on the osteogenesis of periodontal ligament stem cells via crosstalk between the NF-‍κB, MAPK and BMP/Smad signaling pathways. Cell Death Dis, 7(7):e2296.

[55]MengCL, WangX, DuanJM, et al., 2018. The effects TNF-‍α on the proliferation and osteogenic differentiation of periodontal ligament stem cells. China J Conserv Dent, 28(2):63-68 (in Chinese).

[56]MengTT, ZhouY, LiJK, et al., 2018. Azithromycin promotes the osteogenic differentiation of human periodontal ligament stem cells after stimulation with TNF-‍α. Stem Cells Int, 2018:7961962.

[57]MisawaMYO, Silvério RuizKG, NocitiFH, et al., 2019. Periodontal ligament-derived mesenchymal stem cells modulate neutrophil responses via paracrine mechanisms. J Periodontol, 90(7):747-755.

[58]NajiA, EitokuM, FavierB, et al., 2019. Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci, 76(17):3323-3348.

[59]NanbaraH, Wara-AswapatiN, NagasawaT, et al., 2012. Modulation of Wnt5a expression by periodontopathic bacteria. PLoS ONE, 7(4):e34434.

[60]NieJ, ZhangB, GuB, et al., 2015. Effects of p38 mitogen-activated protein kinase on osteogenic differentiation of human periodontal ligament stem cells in inflammatory microenvironment. Acta Acad Med Sin, 37(1):‍1-7 (in Chinese).

[61]OngaroA, PellatiA, BagheriL, et al., 2016. Characterization of Notch signaling during osteogenic differentiation in human osteosarcoma cell line MG63. J Cell Physiol, 231(12):2652-2663.

[62]PanWY, WangQX, ChenQM, 2019. The cytokine network involved in the host immune response to periodontitis. Int J Oral Sci, 11(3):30.

[63]PengY, KangQ, ChengHW, et al., 2003. Transcriptional characterization of bone morphogenetic proteins (BMPs)‍-mediated osteogenic signaling. J Cell Biochem, 90(6):1149-1165.

[64]QiuSC, LongY, ChenXY, et al., 2019. Effects of overexpression of Notch intracellular domain on proliferation and osteogenic differentiation of human periodontal ligament stem cells. Chin J Stomatol, 54(5):‍315-321 (in Chinese).

[65]ShenS, SunSJ, GeSH, 2021. Wnt3a promotes osteogenic differentiation of periodontal ligament stem cell and regeneration of alveolar bone in experimental periodontitis. Chin J Stomatol, 56(3):268-275 (in Chinese).

[66]ShiJM, WuYH, GengSG, et al., 2014. Proliferation, senescence and differentiation of mesenchymal stem cells: canonical and non-canonical regulations of Wnt signaling pathway. Chin J Tissue Eng Res, 18(41):‍6719-6724 (in Chinese).

[67]ShiWP, LingDH, ZhangFY, et al., 2021. Curcumin promotes osteogenic differentiation of human periodontal ligament stem cells by inducting EGR1 expression. Arch Oral Biol, 121:104958.

[68]ShiYF, WangY, LiQ, et al., 2018. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol, 14(8):493-507.

[69]ShinC, KimM, HanJA, et al., 2017. Human periodontal ligament stem cells suppress T-cell proliferation via down-regulation of non-classical major histocompatibility complex-like glycoprotein CD1b on dendritic cells. J Periodontal Res, 52(1):135-146.

[70]SongCQ, MaQ, LiLX, 2019. Studies on regulation mechanism of PERK pathway on osteogenic differentiation ability of periodontal ligament stem cell in inflammatory microenvironment. Biomed Eng Clin Med, 23(4):‍467-475 (in Chinese).

[71]StadlerAF, AngstPDM, ArceRM, et al., 2016. Gingival crevicular fluid levels of cytokines/chemokines in chronic periodontitis: a meta-analysis. J Clin Periodontol, 43(9):727-745.

[72]SuXX, LeiFZ, WangR, et al., 2020. The influence of inflammatory micro-environment on regenerative capacity of PDLSCs and UCMSCs. Oral Biomed, 11(2):‍71-75 (in Chinese).

[73]TakPP, FiresteinGS, 2001. NF-κB: a key role in inflammatory diseases. J Clin Invest, 107(1):7-11.

[74]TanJ, ZhouLH, XueP, et al., 2016. Tumor necrosis factor-‍α attenuates the osteogenic differentiation capacity of periodontal ligament stem cells by activating PERK signaling. J Periodontol, 87(8):e159-e171.

[75]TangRL, WeiFL, WeiLM, et al., 2014. Osteogenic differentiated periodontal ligament stem cells maintain their immunomodulatory capacity. J Tissue Eng Regen Med, 8(3):‍226-232.

[76]TangY, LiuL, WangP, et al., 2017. Periostin promotes migration and osteogenic differentiation of human periodontal ligament mesenchymal stem cells via the Jun amino-terminal kinases (JNK) pathway under inflammatory conditions. Cell Prolif, 50(6):e12369.

[77]TomaselloL, MauceriR, CoppolaA, et al., 2017. Mesenchymal stem cells derived from inflamed dental pulpal and gingival tissue: a potential application for bone formation. Stem Cell Res Ther, 8:179.

[78]TonettiMS, GreenwellH, KornmanKS, 2018. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. J Periodontol, 89(S1):S159-S172.

[79]WangDX, CaoH, HuaWZ, et al., 2022. Mesenchymal stem cell-derived extracellular vesicles for bone defect repair. Membranes, 12(7):716.

[80]WangF, ChenX, HanY, et al., 2019. CircRNA CDR1as regulated the proliferation of human periodontal ligament stem cells under a lipopolysaccharide-induced inflammatory condition. Mediators Inflamm, 2019:1625381.

[81]WangP, WeiLB, NiGX, et al., 2020. Effect of TNF-‍α on autophagy of bone marrow mesenchymal and periodontal membrane. J Mod Stomatol, 34(1):14-16 (in Chinese).

[82]WangPC, TianH, ZhangZ, et al., 2021. EZH2 regulates lipopolysaccharide-induced periodontal ligament stem cell proliferation and osteogenesis through TLR4/MyD88/NF-κB pathway. Stem Cells Int, 2021:7625134.

[83]WangQ, DingG, XuX, 2017. Periodontal ligament stem cells regulate apoptosis of neutrophils. Open Med, 12(1):19-23.

[84]WangW, YuanCY, GengTY, et al., 2020. Lipopolysaccharide inhibits osteogenic differentiation of periodontal ligament stem cells partially through Toll-like receptor 4-mediated ephrinB2 downregulation. Clin Oral Investig, 24(10):3407-3416.

[85]WangYL, YangCC, 2022. Enhanced VEGF-A expression and mediated angiogenic differentiation in human gingival fibroblasts by stimulating with TNF-‍α in vitro. J Dent Sci, 17(2):876-881.

[86]WangYZ, ZhangXG, WangJJ, et al., 2022. Inflammatory periodontal ligament stem cells drive M1 macrophage polarization via exosomal miR-143-3p-mediated regulation of PI3K/AKT/NF-‍κB signaling. Stem Cells, 41(2):184-199.

[87]WeiK, XieYS, ChenTY, et al., 2017. ERK1/2 signaling mediated naringin-induced osteogenic differentiation of immortalized human periodontal ligament stem cells. Biochem Biophys Res Commun, 489(3):319-325.

[88]WuL, WeiQZ, LvYJ, et al., 2019. Wnt/β‍-catenin pathway is involved in cadmium-induced inhibition of osteoblast differentiation of bone marrow mesenchymal stem cells. Int J Mol Sci, 20(6):1519.

[89]XingYX, ZhangYP, JiaLL, et al., 2019. Lipopolysaccharide from Escherichia coli stimulates osteogenic differentiation of human periodontal ligament stem cells through Wnt/β‍-catenin-induced TAZ elevation. Mol Oral Microbiol, 34(1):1-13.

[90]XiongYX, ZhaoB, ZhangWJ, et al., 2020. Curcumin promotes osteogenic differentiation of periodontal ligament stem cells through the PI3K/AKT/Nrf2 signaling pathway. Iran J Basic Med Sci, 23(7):954-960.

[91]YanBB, ZhangHM, DaiTQ, et al., 2018a. Necrostatin-1 promotes ectopic periodontal tissue like structure regeneration in LPS-treated PDLSCs. PLoS ONE, 3(11):e0207760.

[92]YanBB, WeiKW, HouLP, et al., 2018b. Receptor-interacting protein 3/caspase-8 may regulate inflammatory response and promote tissue regeneration in the periodontal microenvironment. Med Sci Monit, 24:LBR5247-5257.

[93]YangH, GaoLN, AnY, et al., 2013. Comparison of mesenchymal stem cells derived from gingival tissue and periodontal ligament in different incubation conditions. Biomaterials, 34(29):7033-7047.

[94]YangY, WangT, ZhangSC, et al., 2021. Vitamin C alleviates the senescence of periodontal ligament stem cells through inhibition of Notch3 during long-term culture. J Cell Physiol, 236(2):1237-1251.

[95]YuBH, LiQ, ZhouM, 2019. LPS-induced upregulation of the TLR4 signaling pathway inhibits osteogenic differentiation of human periodontal ligament stem cells under inflammatory conditions. Int J Mol Med, 43(6):2341-2351.

[96]YuD, WangJ, QianKJ, et al., 2020. Effects of nanofibers on mesenchymal stem cells: environmental factors affecting cell adhesion and osteogenic differentiation and their mechanisms. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(11):871-884.

[97]ZhaiQM, LiB, WangZW, et al., 2018. Endoplasmic reticulum-mitochondrial contact regulates osteogenic differentiation of periodontal ligament stem cells via mitofusion 2 in inflammatory microenvironment. Chin J Stomatol, 53(7):453-458 (in Chinese).

[98]ZhangF, SiMS, WangHM, et al., 2017. IL-1/TNF-α inflammatory and anti-inflammatory synchronization affects gingival stem/progenitor cells’ regenerative attributes. Stem Cells Int, 2017:1349481.

[99]ZhangKK, GengYD, WangSB, et al., 2019. MicroRNA-26a-5p targets Wnt5a to regulate osteogenic differentiation of human periodontal ligament stem cell from inflammatory microenvironment. Chin J Stomatol, 54(10):‍662-669 (in Chinese).

[100]ZhangL, HeHY, ZhangM, et al., 2021. Assessing the effect and related mechanism of naringenin on the proliferation, osteogenic differentiation and endothelial differentiation of human periodontal ligament stem cells. Biochem Biophys Res Commun, 534:337-342.

[101]ZhangWJ, JiaLL, ZhaoB, et al., 2021. Quercetin reverses TNF-α induced osteogenic damage to human periodontal ligament stem cells by suppressing the NF-‍κB/NLRP3 inflammasome pathway. Int J Mol Med, 47(4):39.

[102]ZhangXS, ChenHL, WangZG, 2021. The regulatory effect of Porphyromonas gingivalis infection on osteogenic differentiation of periodontal ligament stem cells through Wnt pathway. Chin J Microecol, 33(1):47-50 (in Chinese).

[103]ZhangY, WangYZ, FeiDD, et al., 2021. Inflammatory periodontal stem cells mediate interleukin-1β secretion of macrophage by regulating macrophage endoplasmic reticulum stress. Chin J Stomatol, 56(4):‍329-334 (in Chinese).

[104]ZhangYL, LiuF, LiZB, et al., 2022. Metformin combats high glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells via inhibition of the NPR3-mediated MAPK pathway. Stem Cell Res Ther, 13:305.

[105]ZhaoB, XiongYX, ZhangYP, et al., 2020a. Rutin promotes osteogenic differentiation of periodontal ligament stem cells through the GPR30-mediated PI3K/AKT/mTOR signaling pathway. Exp Biol Med, 245(6):552-561.

[106]ZhaoB, ZhangWJ, XiongYX, et al., 2020b. Rutin protects human periodontal ligament stem cells from TNF-‍α induced damage to osteogenic differentiation through suppressing mTOR signaling pathway in inflammatory environment. Arch Oral Biol, 109:104584.

[107]ZhengMM, ZhangFP, FanWG, et al., 2020. Suppression of osteogenic differentiation and mitochondrial function change in human periodontal ligament stem cells by melatonin at physiological levels. PeerJ, 8:e8663.

[108]ZhengY, DongC, YangJL, et al., 2019. Exosomal microRNA-155-5p from PDLSCs regulated Th17/Treg balance by targeting sirtuin-1 in chronic periodontitis. J Cell Physiol, 234(11):20662-20674.

[109]ZhouLL, DörferCE, ChenLL, et al., 2017. Porphyromonas gingivalis lipopolysaccharides affect gingival stem/progenitor cells attributes through NF-κB, but not Wnt/β-catenin, pathway. J Clin Periodontol, 44(11):1112-1122.

[110]ZhouLL, LiuW, WuYM, et al., 2020. Oral mesenchymal stem/progenitor cells: the immunomodulatory masters. Stem Cells Int, 2020:1327405.

[111]ZhuWJ, TanYY, QiuQH, et al., 2013. Comparison of the properties of human CD146⁺ and CD146^- periodontal ligament cells in response to stimulation with tumour necrosis factor α. Arch Oral Biol, 58(12):1791-1803.

[112]ZhuWJ, QiuQH, LuoHY, et al., 2020. High glucose exacerbates TNF-‍α‍-induced proliferative inhibition in human periodontal ligament stem cells through upregulation and activation of TNF receptor 1. Stem Cells Int, 2020:4910767.