Jiang Shangzhou, Lin Youkai, Huang Dingming, Tan Xuelian
State Key Laboratory of Oral Diseases & National Center of Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Stem Cells Dev. 2025 Sep;34(17-18):374-384. doi: 10.1177/15473287251366979. Epub 2025 Aug 12.
The dental pulp not only serves as the tooth's nutritional core but also creates a finely tuned microenvironment that is enriched with blood vessels, nerves, extracellular matrix components, and signaling molecules, all of which guide the fate of resident dental pulp stem cells (DPSCs). Trauma and microbial invasion disrupt this niche, leading to pulpitis and necrosis. Although conventional root canal treatment preserves the tooth's structure by removing infected pulp, it can increase tooth brittleness and impede root development in immature permanent teeth. Harnessing DPSCs' multipotency for pulp regeneration promises to restore the natural pulp-dentin complex in situ. Importantly, DPSCs encounter an inflammatory microenvironment composed of pathogen-associated molecular patterns, a spectrum of pro- and anti-inflammatory cytokines, diverse immune cell phenotypes, and altered matrix signals. While earlier work examined the isolated effects of mediators such as lipopolysaccharide, tumor necrosis factor-alpha, or macrophage-derived exosomes on odontogenic differentiation, this review focuses on how these mediators collectively interact in both synergistic and antagonistic ways within the inflammatory niche. We systematically delineate how these collective stimuli converge on wingless/integrated/beta-catenin, mitogen-activated protein kinase, nuclear factor kappa-B (NF-κB), and bone morphogenetic protein/Sma and Mad related protein pathways to modulate key odontogenic markers (runt-related transcription factor 2, dentin sialophosphoprotein, dentin matrix protein 1, alkaline phosphatase) and mineralization outcomes. By applying a microenvironment-centric lens, we reveal novel targets and strategies to recalibrate inflammation, steer DPSCs toward reparative odontogenesis, and ultimately enhance the efficacy of regenerative endodontic therapies.
牙髓不仅是牙齿的营养核心，还营造了一个经过精细调节的微环境，其中富含血管、神经、细胞外基质成分和信号分子，所有这些都引导着驻留牙髓干细胞（DPSC）的命运。创伤和微生物入侵会破坏这个生态位，导致牙髓炎和坏死。尽管传统的根管治疗通过去除感染的牙髓来保留牙齿结构，但它会增加牙齿脆性，并阻碍未成熟恒牙的牙根发育。利用DPSC的多能性进行牙髓再生有望原位恢复天然的牙髓-牙本质复合体。重要的是，DPSC会遇到由病原体相关分子模式、一系列促炎和抗炎细胞因子、多种免疫细胞表型以及改变的基质信号组成的炎症微环境。虽然早期的研究考察了诸如脂多糖、肿瘤坏死因子-α或巨噬细胞衍生的外泌体等介质对牙源性分化的单独影响，但本综述重点关注这些介质如何在炎症生态位内以协同和拮抗的方式共同相互作用。我们系统地描述了这些共同刺激如何汇聚到无翅/整合/β-连环蛋白、丝裂原活化蛋白激酶、核因子κB（NF-κB）和骨形态发生蛋白/Sma和Mad相关蛋白途径上，以调节关键的牙源性标志物（ runt相关转录因子2、牙本质涎磷蛋白、牙本质基质蛋白1、碱性磷酸酶）和矿化结果。通过以微环境为中心的视角，我们揭示了重新校准炎症、引导DPSC走向修复性牙生成并最终提高再生性牙髓治疗疗效的新靶点和策略。
