Journal: Bioactive Materials

Article Title: Microenvironment-mediated stem cell fate in periodontal tissue remodeling and repair

doi: 10.1016/j.bioactmat.2025.12.025

Figure Lengend Snippet: Comparisons of physiological and periodontitis microenvironments. In physiological conditions, factors in the microenvironment that directly interact with the residing MSCs include the ECM, growth factors, hormones and neighboring cells such as immune cells, endothelial cells and other MSCs. A healthy, well-organized ECM supports the adhesion, proliferation and tissue-specific differentiation of MSCs. Growth factors such as TGF-β1, PDGF and FGF-2 foster MSC proliferation and fibrogenic differentiation, whereas IGF-1 facilitates osteogenesis. PTHrP/PPR signaling in DFSCs plays a critical role in root formation and tooth eruption. Macrophages, endothelial cells and MSCs in normal conditions all favor tissue-specific differentiation of MSCs, especially osteogenic differentiation in the periodontal context. In periodontitis conditions, bacterial invasion of the local microenvironment directly suppresses MSC osteogenic differentiation through PAMPs and virulence factors. Excessive ROS generation further impairs MSC osteogenesis, while hypoxia exerts context-dependent effects on MSC fate. In addition, MMP-mediated ECM degradation reduces matrix stiffness and compromises the osteogenic capacity of MSCs. The expression of proinflammatory cytokines in gingival crevicular fluid and periodontal tissues is increased, including IL-1 family members (IL-1β, IL-18, IL-33, IL-36β and IL-36γ), IL-6, TNFα, IL-17, IL-12 and IL-23. High levels of proinflammatory cytokines inhibit the osteogenic differentiation of MSCs and may further stimulate the secretion of proinflammatory cytokines. Meanwhile, inflamed macrophages secrete proinflammatory exosomes that hinder the osteogenic differentiation of MSCs. Notably, some inflamed MSCs can release immunomodulatory exosomes that promote M2 macrophage polarization to mitigate inflammation. Created with BioRender.com .

Article Snippet: Physiological microenvironment , PDLSCs , ECM , RhoA/ROCK signaling , Osteogenic differentiation↑ Collagen-I and fibronectin production↑ Cytoskeleton formation↑ , [ , , ] .

Techniques: Expressing

Journal: Bioactive Materials

Article Title: Microenvironment-mediated stem cell fate in periodontal tissue remodeling and repair

doi: 10.1016/j.bioactmat.2025.12.025

Figure Lengend Snippet: Interactions between the microenvironment and stem cells in periodontal injuries. In periodontal bone fracture, N2-neutrophils are initially recruited to injury sites and secrete SDF-1α to recruit BMSCs. The recruitment of BMSCs to injury sites enables further osteogenesis and matrix production, contributing to fracture healing. MSCs induce M2 polarization in macrophages, and M2 macrophages in turn facilitate osteogenic differentiation in BMSCs partly via exosomes. The increased expression of AMBN in the ECM during bone fracture promotes the osteogenic and chondrogenic differentiation of BMSCs. In gingival injuries, the influx of blood brings thrombin, PDGF-BB, TGF-β, LPA, proteases and chemokines into interstitial tissues, activating local fibroblasts to recruit immune cells via IL-8 secretion. Immune cells promote the activation of fibroblasts in a feedback loop, aggravating the local inflammatory response. PDGF-BB and TGF-β stimulate fibroblast proliferation, migration and ECM production. In response to PDGF, LPA and thrombin, migratory fibroblasts further differentiate into myofibroblasts, which are distributed along wound margins to facilitate wound contraction. Created with BioRender.com .

Article Snippet: Physiological microenvironment , PDLSCs , ECM , RhoA/ROCK signaling , Osteogenic differentiation↑ Collagen-I and fibronectin production↑ Cytoskeleton formation↑ , [ , , ] .

Techniques: Expressing, Activation Assay, Migration

Journal: Bioactive Materials

Article Title: Microenvironment-mediated stem cell fate in periodontal tissue remodeling and repair

doi: 10.1016/j.bioactmat.2025.12.025

Figure Lengend Snippet: Tackling the inflammatory microenvironment. Killing bacteria, immunoregulation and ROS clearance are effective strategies to control inflammation. The emergence of antibacterial nanoparticles, such as nMgO and nAg, as well as antibacterial polypeptides, helps overcome the practical limitations when antibiotics are incorporated into materials. The encapsulation and controlled release of immunoregulatory biomolecules is a strategy for immunoregulation. The controlled release of IL-2, TGF-β and miR-10a achieved by MSNs and PLGA MS facilitates the recruitment and differentiation of Tregs. Metal elements and nanomaterials provide alternative solutions. Mo, AuNPs and some polypeptides induce M2 macrophage polarization. When combined with quercetin, the nano-octahedral ceria-based composite inhibits M1 polarization, facilitates M2 polarization, downregulates proinflammatory cytokines and upregulates anti-inflammatory cytokines. Building an ROS clearing platform with ROS scavengers such as PDA, NAC, CoO, Prussian blue (PB) and Mn not only protects stem cells from oxidative damage but also alleviates inflammation and enhances bone formation. Created with BioRender.com .

Article Snippet: Physiological microenvironment , PDLSCs , ECM , RhoA/ROCK signaling , Osteogenic differentiation↑ Collagen-I and fibronectin production↑ Cytoskeleton formation↑ , [ , , ] .

Techniques: Bacteria, Control, Encapsulation

Journal: Bioactive Materials

Article Title: Microenvironment-mediated stem cell fate in periodontal tissue remodeling and repair

doi: 10.1016/j.bioactmat.2025.12.025

Figure Lengend Snippet: Schematic illustration of stem cell interactions with various biomaterials in periodontal regeneration. Biomaterials closely interact with stem cells to support periodontal regeneration. MSC-laden mineralized hydrogels mimic the cellular, structural, and chemical features of bone autografts, activating RhoA/ROCK signaling, inducing YAP nuclear translocation, and upregulating RUNX2 expression in encapsulated MSCs. Phosphate ions in the mineralization medium and matrix further enhance ATP and adenosine production, with adenosine binding to A2b receptors to drive osteogenesis . GTR/GBR membranes facilitate adhesion, proliferation, and osteogenic differentiation of recruited stem cells through bioactive components such as PDA, AMP, β-TCP, and CeO2 NPs [ , , , ]. Various scaffold systems also contribute to regeneration. A tetra-PEG network incorporating chitosan enables sustained release of ASA, which promotes bone formation via T-cell suppression and enhances PDLSC osteogenesis while inducing M2 macrophage polarization through upregulated MCP-1 secretion . Electroactive mineralized scaffolds activate voltage-gated Ca 2+ channels and ATP-mediated cytoskeletal remodeling, promoting MSC osteogenesis through the BMP2/Smad5 pathway . A tissue-specific scaffold combining aligned MEW PCL fibers with F/CaP-coated fibers supports ligamentogenic and osteogenic differentiation of PDLSCs . Furthermore, materials engineered with specific mechanobiological features, such as anisotropic surface potential, magnetism, viscoelasticity, and optimized elastic modulus, enhance MSC osteogenic differentiation via mechanotransduction pathways [ , , ]. Created with BioRender.com .

Article Snippet: Physiological microenvironment , PDLSCs , ECM , RhoA/ROCK signaling , Osteogenic differentiation↑ Collagen-I and fibronectin production↑ Cytoskeleton formation↑ , [ , , ] .

Techniques: Translocation Assay, Expressing, Binding Assay