M2 Macrophages Enhance the Cementoblastic Differentiation of Periodontal Ligament Stem Cells via the Akt and JNK Pathways

Abstract

Although macrophage (Mφ) polarization has been demonstrated to play crucial roles in cellular osteogenesis across the cascade of events in periodontal regeneration, how polarized Mφ phenotypes influence the cementoblastic differentiation of periodontal ligament stem cells (PDLSCs) remains unknown. In the present study, human monocyte leukemic cells (THP‐1) were induced into M0, M1, and M2 subsets, and the influences of these polarized Mφs on the cementoblastic differentiation of PDLSCs were assessed in both conditioned medium‐based and Transwell‐based coculture systems. Furthermore, the potential pathways and cyto‐/chemokines involved in Mφ‐mediated cementoblastic differentiation were screened and identified. In both systems, M2 subsets increased cementoblastic differentiation‐related gene/protein expression levels in cocultured PDLSCs, induced more PDLSCs to differentiate into polygonal and square cells, and enhanced alkaline phosphatase activity in PDLSCs. Furthermore, Akt and c‐Jun N‐terminal Kinase (JNK) signaling was identified as a potential pathway involved in M2 Mφ‐enhanced PDLSC cementoblastic differentiation, and cyto‐/chemokines (interleukin (IL)‐10 and vascular endothelial growth factor [VEGF]) secreted by M2 Mφs were found to be key players that promoted cell cementoblastic differentiation by activating Akt signaling. Our data indicate for the first time that Mφs are key modulators during PDLSC cementoblastic differentiation and are hence very important for the regeneration of multiple periodontal tissues, including the cementum. Although the Akt and JNK pathways are involved in M2 Mφ‐enhanced cementoblastic differentiation, only the Akt pathway can be activated via a cyto‐/chemokine‐associated mechanism, suggesting that players other than cyto‐/chemokines also participate in the M2‐mediated cementoblastic differentiation of PDLSCs. Stem Cells 2019;37:1567–1580

Dental-Derived Mesenchymal Stem Cells: State of the Art

“…A potential link between WNT signaling and the plasminogenplasmin pathway to control cementogenic differentiation has been reported (Martins et al, 2020). Besides, the PI3K/AKT and JNK pathways have also been identified to participate in the enhanced cementogenesis of PDLSCs, which can be activated by M2 macrophages through cytokine and/or chemokine secretion, in particular, interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF) (Li et al, 2019).…”

Tanyu Tongzhi Formula Delays Atherosclerotic Plaque Progression by Promoting Alternative Macrophage Activation via PPARγ and AKT/ERK Signal Pathway in ApoE Knock-Out Mice

“…There is a definite interaction between AKT signaling and alternative macrophage activation, and AKT signaling participates in alternative macrophage-enhanced differentiation of periodontal ligament stem cell cementoblastic differentiation ( Li et al, 2019 ). However, alternative macrophage activation functions by activating the phosphorylation of Akt in multiple sclerosis animal models ( Weng et al, 2019 ).…”

Elements of 3D Bioprinting in Periodontal Regeneration: Frontiers and Prospects

“…Panduwawala CP et al co-cultured PDLSCs with human umbilical vein endothelial cells in immunodeficiency mice and found new periodontal ligament regenerated at weeks 4 and 8 [44]. Xuan et al co-cultured M2 macrophages and PDLSCs, which can promote the matrix differentiation of PDLSCs [22]. In vivo, PDLSCs can both differentiate into bonelike mineral tissue and ligament-like fibric tissue with a certain arrangement depending on different growth factors.…”