Department of Endodontics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, 93053 Regensburg, Germany.
Cells. 2023 Oct 21;12(20):2502. doi: 10.3390/cells12202502.
Regenerative therapies to replace cells and tissues damaged due to trauma and dental infections require temporal and spatial controlled recruitment and the differentiation of progenitor/stem cells. However, increasing evidence shows microbial antigens can interfere with this process. Toll-like receptors (TLRs) are crucial in recognizing pathogen-associated molecular patterns. Stem cells of the apical papilla (SCAP) are required for normal dental development and are intimately involved in the reparative and regenerative capacity of developing teeth. We hypothesized that TLRs are expressed in SCAP and that the activation of TLR2/TLR4 or TLR3 by different ligands results in differential cellular fate, impacting their differentiation into a mineralizing phenotype. We found that most TLRs are expressed as detected by PCR except TLR7 and TLR8; exposure to heat-killed E. coli results in upregulating TLR2 and TLR4 and reducing mineralization capacity. In addition, bacterial exposure resulted in the upregulation of 11 genes, of which 9 were chemokines whose proteins were also upregulated and released, promoting in vitro macrophage migration. On the other hand, TLR3 activation resulted in increased proliferation and a dramatic inhibition of osteogenic and odontoblastic differentiation, which was reversed by inhibition or the knockdown of TLR3 expression. The profound effects of TLR activation resulting in different cell fates that are ligand and receptor-specific warrants further evaluation and represents an important therapeutic target to make regenerative approaches more predictable following dental infections.
再生疗法旨在替换因创伤和口腔感染而受损的细胞和组织，需要对祖细胞/干细胞进行时空控制募集和分化。然而，越来越多的证据表明，微生物抗原会干扰这一过程。Toll 样受体 (TLR) 在识别病原体相关分子模式方面起着至关重要的作用。根尖乳头干细胞 (SCAP) 是正常牙齿发育所必需的，并且与发育中牙齿的修复和再生能力密切相关。我们假设 TLR 在 SCAP 中表达，并且不同配体激活 TLR2/TLR4 或 TLR3 会导致细胞命运的差异，从而影响它们向矿化表型的分化。我们发现，除 TLR7 和 TLR8 外，PCR 检测到大多数 TLR 都有表达；热灭活的大肠杆菌暴露会导致 TLR2 和 TLR4 的上调以及矿化能力的降低。此外，细菌暴露导致 11 个基因上调，其中 9 个是趋化因子，其蛋白质也上调并释放，从而促进体外巨噬细胞迁移。另一方面，TLR3 的激活导致增殖增加，成骨和成牙本质分化受到显著抑制，而 TLR3 表达的抑制或敲低则逆转了这种抑制作用。TLR 激活导致不同的细胞命运，这种命运具有配体和受体特异性，需要进一步评估，这代表了一个重要的治疗靶点，可以使再生方法在口腔感染后更具可预测性。
