Stem cells maintain a subtle balance between self-renewal and differentiation under the regulatory network supported by both intracellular and extracellular components. Proteoglycans are large glycoproteins present abundantly on the cell surface and in the extracellular matrix where they play pivotal roles in facilitating signaling transduction and maintaining stem cell homeostasis. In this review, we outline distinct proteoglycans profiles and their functions in the regulation of stem cell homeostasis, as well as recent progress and prospects of utilizing proteoglycans/glycosaminoglycans as a novel glycomics carrier or bio-active molecules in bone regeneration.

Tooth development and regeneration are regulated through a complex signaling network. Previous studies have focused on the exploration of intracellular signaling regulatory networks, but the regulatory roles of extracellular networks have only been revealed recently. Proteoglycans, which are essential components of the extracellular matrix (ECM) and pivotal signaling molecules, are extensively involved in the process of odontogenesis. Proteoglycans are composed of core proteins and covalently attached glycosaminoglycan chains (GAGs). The core proteins exhibit spatiotemporal expression patterns during odontogenesis and are pivotal for dental tissue formation and periodontium development. Knockout of core protein genes Biglycan, Decorin, Perlecan, and Fibromodulin has been shown to result in structural defects in enamel and dentin mineralization. They are also closely involved in the development and homeostasis of periodontium by regulating signaling transduction. As the functional component of proteoglycans, GAGs are negatively charged unbranched polysaccharides that consist of repeating disaccharides with various sulfation groups; they provide binding sites for cytokines and growth factors in regulating various cellular processes. In mice, GAG deficiency in dental epithelium leads to the reinitiation of tooth germ development and the formation of supernumerary incisors. Furthermore, GAGs are critical for the differentiation of dental stem cells. Inhibition of GAGs assembly hinders the differentiation of ameloblasts and odontoblasts. In summary, core proteins and GAGs are expressed distinctly and exert different functions at various stages of odontogenesis. Given their unique contributions in odontogenesis, this review summarizes the roles of proteoglycans and GAGs throughout the process of odontogenesis to provide a comprehensive understanding of tooth development.

Background: Human dental pulp stem cells (hDPSCs) play an important role in endodontic regeneration. N6-methyladenosine (m⁶A) is the most common RNA modification, and noncoding RNAs have also been demonstrated to have regulatory roles in the expression of m⁶A regulatory proteins. However, the study on m⁶A modification in hDPSCs has not yet been conducted. Methods: Single base site PCR (MazF) was used to detect the m⁶A modification site of lncSNHG7 before and after mineralization of hDPSCs to screen the target m⁶A modification protein, and bioinformatics analysis was used to analyze the related pathways rich in lncSNHG7. After knockdown and overexpression of lncSNHG7 and METTL3, the osteogenic/odontogenic ability was detected. After METTL3 knockdown, the m⁶A modification level and its expression of lncSNHG7 were detected by MazF, and their binding was confirmed. Finally, the effects of lncSNHG7 and METTL3 on the Wnt/β-catenin pathway were detected. Results: MazF experiments revealed that lncSNHG7 had a m⁶A modification before and after mineralization of hDPSCs, and the occurrence site was 2081. METTL3 was most significantly upregulated after mineralization of hDPSCs. Knockdown/ overexpression of lncSNHG7 and METTL3 inhibited/promoted the osteogenic/odontogenic differentiation of hDPSCs. The m⁶A modification and expression of lncSNHG7 were both regulated by METTL3. Subsequently, lncSNHG7 and METTL3 were found to regulate the Wnt/β-catenin signaling pathway. Conclusion: These results revealed that METTL3 can activate the Wnt/β-catenin signaling pathway by regulating the m⁶A modification and expression of lncSNHG7 in hDPSCs to enhance the osteogenic/odontogenic differentiation of hDPSCs. Our study provides new insight into stem cell-based tissue engineering.

Background: Periodontitis is a chronic immune‐mediated inflammatory disease characterized by the progressive degradation of periodontal tissues. Conventional therapies, including anti‐inflammatory agents and antibiotics, are limited by systemic adverse effects and increased microbial resistance, highlighting the need for safer, multi‐targeted treatments. Objective: This review systematically evaluates the therapeutic potential of plant‐ and fungal‐derived polysaccharides in periodontitis treatment. It focuses on their multifaceted biological activities, including anti‐inflammatory, antioxidant, antimicrobial, and osteo‐regenerative effects, and elucidates key molecular mechanisms, such as nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐ κ B), mitogen‐activated protein kinase (MAPK), Wnt/ β ‐catenin, and BMP‐2/Smad signaling pathways. Additionally, it identifies current research gaps and proposes strategies to facilitate the translational development of polysaccharide‐based therapies. Materials and Methods: A systematic literature search was performed across PubMed, Scopus, Web of Science, and Google Scholar databases using a combination of Medical Subject Heading (MeSH) terms and keywords, including “periodontitis,” “plant polysaccharides,” “fungal polysaccharides,” “inflammatory factors,” and “bone regeneration.” A total of 104 studies were included after screening for relevance to the therapeutic roles and molecular mechanisms of plant‐ and fungal‐derived polysaccharides in periodontitis. The dataset encompassed both in vitro and in vivo investigations, and narrative synthesis was employed to integrate findings owing to the substantial heterogeneity in study designs, endpoints, and methodological approaches. Conclusion: Plant‐ and fungal‐derived polysaccharides have substantial potential as adjunct or alternative therapies for the treatment of periodontitis. Their multifunctional activities, including modulation of inflammation, inhibition of pathogenic biofilms, and promotion of periodontal tissue regeneration, are mediated through complex multi‐pathway interactions. Clinical translation remains limited by structural heterogeneity, a lack of standardized preparation protocols, and insufficient in vivo validation. Future research should prioritize elucidating structure–activity relationships, optimizing extraction and formulation methods, and conducting well‐designed clinical trials. Integrating evidence from 104 studies, this review underscores the anti‐inflammatory, antimicrobial, and osteo‐regenerative effects of these polysaccharides and emphasizes their importance in future clinical applications.