# Cementum regeneration strategies: Insights from development and periodontal microenvironment **Authors:** Huiyi Wang, Liu Yang, Xin Huang, Li Ma, Chuan Wang, Xiaoxuan Wang, Zhengguo Cao PMC · DOI: 10.3389/fcell.2025.1685609 · Frontiers in Cell and Developmental Biology · 2025-10-01 ## TL;DR This review explores strategies for regenerating cementum, a tooth-supporting tissue, by understanding its development and the surrounding periodontal environment. ## Contribution The paper systematically consolidates current knowledge and proposes novel insights for cementum regeneration based on developmental mechanisms and microenvironmental factors. ## Key findings - Cementum regeneration is hindered by the complex periodontal microenvironment involving host cells and microbes. - Research highlights the role of metabolic reprogramming and immune-stem cell interactions in cementum development. - Engineered materials and regulatory mechanisms in cementoblast differentiation are being explored for regeneration. ## Abstract Cementum, a mineralized tissue covering the root surface of the tooth, maintains tooth stability through providing support for the attachment of periodontal ligament fibres, and protects the pulp from external damage via acting as a barrier against microbial invasion and destruction. Notably, both physiological and pathological factors may lead to the destruction of this vulnerable tissue, thus impeding its function. However, the intricate periodontal microenvironment, which consists of host cells, microbial communities, and metabolites, presents challenges to cementum regeneration. In addition, there remains a debate regarding whether the cellular origin of cementum is derived from mesenchymal cells or epithelial cells. Due to the limitations of traditional regenerative surgeries in achieving complete cementum regeneration, researchers are exploring new strategies based on cementum development and the periodontal microenvironment. Our group has revealed the crucial regulatory mechanisms in cementoblast differentiation and developed engineering materials for cementum regeneration. Drawing upon the latest research on cementum development and regeneration, alongside the comprehensive studies undertaken by our research group over the years, this review systematically consolidates current knowledge on cementum development and the regulatory functions of the periodontal microenvironment. It emphasizes mechanisms such as metabolic reprogramming, epigenetic modifications, and immune-stem cell interactions. Furthermore, the review seeks to provide innovative, target-oriented insights for strategies aimed at cementum regeneration, grounded in the understanding of cementum development and the periodontal microenvironment. ## Full-text entities - **Genes:** Smad1 (SMAD family member 1) [NCBI Gene 17125] {aka Mad1, Madh1, Madr1, Mlp1, MusMLP, dwf-A}, Phex (phosphate regulating endopeptidase homolog, X-linked) [NCBI Gene 18675] {aka Gy, HPDR, HPDR1, Hyp, PEX}, Phospho1 (phosphatase, orphan 1) [NCBI Gene 237928] {aka D11Moh36, Phospo1}, Bmp2 (bone morphogenetic protein 2) [NCBI Gene 12156] {aka Bmp2a}, Nfat5 (nuclear factor of activated T cells 5) [NCBI Gene 54446] {aka B130038B15Rik, CAG-8, CAG80, NFATL1, OREBP, TonEBP}, Mmp2 (matrix metallopeptidase 2) [NCBI Gene 17390] {aka Clg4a, GelA, MMP-2}, Ptx3 (pentraxin related gene) [NCBI Gene 19288] {aka TSG-14}, Bmp1 (bone morphogenetic protein 1) [NCBI Gene 12153] {aka Pcp, Tld}, Dnmt3a (DNA methyltransferase 3A) [NCBI Gene 13435] {aka MmuIIIA}, Tlr3 (toll-like receptor 3) [NCBI Gene 142980], Sost (sclerostin) [NCBI Gene 74499] {aka 5430411E23Rik}, Col1a1 (collagen, type I, alpha 1) [NCBI Gene 12842] {aka Col1a-1, Cola-1, Cola1, Mov-13, Mov13}, BMP2 (bone morphogenetic protein 2) [NCBI Gene 650] {aka BDA2, BMP2A, SSFSC, SSFSC1}, SP7 (Sp7 transcription factor) [NCBI Gene 121340] {aka OI11, OI12, OSX, osterix}, Mmp9 (matrix metallopeptidase 9) [NCBI Gene 17395] {aka B/MMP9, Clg4b, Gel B, MMP-9, pro-MMP-9}, Enpp1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) [NCBI Gene 18605] {aka 4833416E15Rik, CD203c, E-NPP 1, E-NPP1, Ly-41, M6S1}, Axin2 (axin 2) [NCBI Gene 12006] {aka Axi1, Axil, Conductin}, BGLAP (bone gamma-carboxyglutamate protein) [NCBI Gene 632] {aka BGP, OC, OCN}, Tet1 (tet methylcytosine dioxygenase 1) [NCBI Gene 52463] {aka 2510010B09Rik, Cxxc6, D10Ertd17e, LCX, mKIAA1676}, Bmp4 (bone morphogenetic protein 4) [NCBI Gene 12159] {aka Bmp-4, Bmp2b, Bmp2b-1, Bmp2b1}, Il2 (interleukin 2) [NCBI Gene 16183] {aka Il-2}, RUNX2 (RUNX family transcription factor 2) [NCBI Gene 860] {aka AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD}, Fto (FTO alpha-ketoglutarate dependent dioxygenase) [NCBI Gene 26383] {aka mKIAA1752}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, Cdkn1a (cyclin dependent kinase inhibitor 1A) [NCBI Gene 12575] {aka CAP20, CDKI, CIP1, Cdkn1, P21, SDI1}, Lrp6 (low density lipoprotein receptor-related protein 6) [NCBI Gene 16974] {aka C030016K15Rik, Cd, Gw, ska26, ska, skax26}, Mul1 (mitochondrial ubiquitin ligase activator of NFKB 1) [NCBI Gene 68350] {aka 0610009K11Rik, Gide, Tnrip-1}, Ccn2 (cellular communication network factor 2) [NCBI Gene 14219] {aka Ctgf, Fisp12, Hcs24, fisp-12}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], Vdr (vitamin D (1,25-dihydroxyvitamin D3) receptor) [NCBI Gene 22337] {aka Nr1i1}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, Gja1 (gap junction protein, alpha 1) [NCBI Gene 14609] {aka Cnx43, Cx43, Cx43alpha1, Cxnk1, Gja-1, Npm1}, Alpl (alkaline phosphatase, liver/bone/kidney) [NCBI Gene 11647] {aka ALP, APTNAP, Akp-2, Akp2, TNAP, TNSALP}, Cd274 (CD274 antigen) [NCBI Gene 60533] {aka A530045L16Rik, B7h1, Pdcd1l1, Pdcd1lg1, Pdl1}, Gli1 (GLI-Kruppel family member GLI1) [NCBI Gene 14632] {aka Zfp-5, Zfp5}, Il1a (interleukin 1 alpha) [NCBI Gene 16175] {aka Il-1a}, Kctd1 (potassium channel tetramerisation domain containing 1) [NCBI Gene 106931] {aka 4933402K10Rik}, Krt14 (keratin 14) [NCBI Gene 16664] {aka CK-14, K14, Krt-1.14, Krt1-14}, Bsp (black spleen) [NCBI Gene 103993], Mdm2 (MDM2 proto-oncogene) [NCBI Gene 17246] {aka 1700007J15Rik, Mdm-2}, Igf1 (insulin-like growth factor 1) [NCBI Gene 16000] {aka C730016P09Rik, Igf-1, Igf-I}, Ctnnb1 (catenin beta 1) [NCBI Gene 12387] {aka Bfc, Catnb, Mesc}, Dkk1 (dickkopf WNT signaling pathway inhibitor 1) [NCBI Gene 13380] {aka mdkk-1}, Wnt1 (wingless-type MMTV integration site family, member 1) [NCBI Gene 22408] {aka Int-1, Wnt-1, sw, swaying}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, Amelx (amelogenin, X-linked) [NCBI Gene 11704] {aka ALGN, AMGL, AMGX, Amel, Amg, LRAP}, Mir155 (microRNA 155) [NCBI Gene 387173] {aka Mirn155, mir-155, mmu-mir-155}, Tlr2 (toll-like receptor 2) [NCBI Gene 24088] {aka Ly105}, Foxo1 (forkhead box O1) [NCBI Gene 56458] {aka Afxh, FKHR, Fkhr1, Foxo1a}, Plekho1 (pleckstrin homology domain containing, family O member 1) [NCBI Gene 67220] {aka 2810052M02Rik, CKIP-1, Ckip1, JZA-20, Jza2}, Wnt3a (wingless-type MMTV integration site family, member 3A) [NCBI Gene 22416] {aka Wnt-3a, vt}, Sp7 (Sp7 transcription factor 7) [NCBI Gene 170574] {aka 6430578P22Rik, C22, Osx}, Ank (progressive ankylosis) [NCBI Gene 11732] {aka Ankh, D15Ertd221e, mKIAA1581}, SPP1 (secreted phosphoprotein 1) [NCBI Gene 6696] {aka BNSP, BSPI, ETA-1, OPN}, Mir10a (microRNA 10a) [NCBI Gene 723893] {aka Mirn10a, miR-10a, mmu-mir-10a} - **Diseases:** resorption (MESH:D014091), root resorption (MESH:D012391), bacterial (MESH:D001424), cementum hyperplasia (MESH:D006965), periodontal disease (MESH:D010510), herpesvirus infection (MESH:D006566), hypoxia (MESH:D000860), alveolar (MESH:D002282), attachment loss (MESH:D017622), apical periodontitis (MESH:D010485), trauma (MESH:D014947), caries (MESH:D003731), hypercementosis (MESH:D006936), periodontal defects (MESH:D010518), Inflammation (MESH:D007249), gingival recession (MESH:D005889), tumors (MESH:D009369), hypophosphatemia (MESH:D017674), Porphyromonas gingivalis infection (MESH:D007239), bone loss (MESH:D001847), periodontal bone defect (MESH:D016301) - **Chemicals:** metformin (MESH:D008687), citric acid (MESH:D019343), methotrexate (MESH:D008727), butyric acid (MESH:D020148), beta-TCP (MESH:C485817), leucine (MESH:D007930), ZnO (MESH:D015034), Prostaglandin E2 (MESH:D015232), LPS (MESH:D008070), lipid (MESH:D008055), arachidonic acid (MESH:D016718), minocycline (MESH:D008911), pyrophosphate (MESH:C107241), simvastatin (MESH:D019821), Eosin (MESH:D004801), NAD+ (MESH:D009243), beta-glucan (MESH:D047071), SCFAs (MESH:D005232), dimethyl sulfides (MESH:C004784), calcium (MESH:D002118), hyaluronic acid (MESH:D006820), CH3SH (MESH:C005231), glucose (MESH:D005947), isovaleric acid (MESH:C008216), Toluidine blue (MESH:D014048), vitamin D (MESH:D014807), H&E (MESH:D006371), H2S (MESH:D006862), Comp-EVs (-), N6-methyladenosine (MESH:C010223), tetracycline (MESH:D013752), zinc (MESH:D015032), Hematoxylin (MESH:D006416), acids (MESH:D000143), chitosan (MESH:D048271), AKG (MESH:D007656), Pi (MESH:D010716), inorganic phosphate (MESH:D010710), titanium (MESH:D014025), Poly (I:C) (MESH:D011070), butyrate (MESH:D002087), Lactate (MESH:D019344), PC (MESH:C053518), TCA (MESH:D014233), fatty acid (MESH:D005227), chitin (MESH:D002686), hydroxyapatite (MESH:D017886), amines (MESH:D000588) - **Species:** Fusobacterium nucleatum (species) [taxon 851], Aggregatibacter actinomycetemcomitans (species) [taxon 714], Porphyromonas gingivalis (species) [taxon 837], Mus musculus (house mouse, species) [taxon 10090], Rattus norvegicus (brown rat, species) [taxon 10116], Felis catus (cat, species) [taxon 9685], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Homo sapiens (human, species) [taxon 9606] - **Mutations:** R26R - **Cell lines:** HERS — Capra hircus (Goat), Finite cell line (CVCL_IR22) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12521119/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12521119/full.md ## References 175 references — full list in the complete paper: https://tomesphere.com/paper/PMC12521119/full.md --- Source: https://tomesphere.com/paper/PMC12521119