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PDLSC-CM targets HAPLN1 in macrophages to reduce root resorption in delayed replanted teeth

ABSTRACT: Background Tooth avulsion is the most serious dental trauma, mainly occurring in the anterior teeth area of adolescents. Delayed tooth replantation is the most common treatment in clinical, but root resorption is a common complication that can lead to tooth loss. However, teenagers cannot receive implant therapy. So how to reduce root resorption and prolong the life span of delayed replanted tooth is a difficult problem in dentistry. We aim to evaluate the therapeutic effect and potential target of periodontal ligament stem cell-conditioned medium (PDLSC-CM) to reduce root resorption in delayed replanted tooth. Methods X-ray imaging and histological staining were applied to evaluate tissue status and relevant factors expression in clinical specimens from patients with delayed replanted teeth. A rat delayed tooth replantation model was established. PDLSC-CM served as both the tooth preservation medium and alveolar cavity flushing solution. Root resorption and relevant factors were assessed by micro-CT and histopathology. Proteomic analysis identified differentially expressed proteins in CM-treated tissue, validated by Western blot and immunofluorescence. In vitro, bone marrow-derived macrophages and RAW264.7 cells were used to investigate macrophage osteoclastogenic differentiation and polarization. Adenovirus was constructed to validate the key protein molecules. Results Human avulsed tooth with delayed replantation shows obvious root resorption and high expressions of inflammatory cytokines and osteoclast-related factors in periapical tissue. PDLSC-CM reduces the root resorption and inhibits the expressions of inflammatory cytokines and osteoclast-related factors in root and periapical tissue of delayed replantation of avulsed tooth in rats. PDLSC-CM downregulates the expression of HAPLN1 mainly in macrophages, thereby inhibits inflammation and osteoclastogenesis of delayed replanted tooth root. Overexpression of HAPLN1 abolishes the protective effect of PDLSC-CM on delayed replanted tooth root. Conclusion HAPLN1 reduction in macrophages plays a pivotal role in PDLSC-CM reducing root resorption. PDLSC-CM is a promising preservation medium for avulsed teeth with potential clinical applications, and the development of drug candidate targeting HAPLN1 has favorable clinical prospects.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Huijie Ma

PROVIDER: PXD073046 | iProX | Wed Jan 14 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Intervertebral disc (IVD) degeneration is a common pathological condition associated with low back pain. Recent evidence suggests that MSCs promote IVD regeneration, but underlying mechanisms remain poorly defined. One postulated mechanism is via modulation of macrophage phenotypes. MSCs encounter drastic declines in oxygen tension when injected into the avascular IVD; thus, understanding how oxygen tension affects interactions between MSCs and macrophages may offer clues as to how MSCs act therapeutically. We investigated how conditioned medium (CM) derived from MSCs cultured in hypoxia altered macrophage subsets. We cultured human, bone marrow-derived STRO3+ MSCs in hypoxia or normoxia, and collected CM. We then cultured human bone marrow-derived macrophages with IFN-y, followed by either hypoxic or normoxic STRO3+ MSC CM. We also cultured macrophages in hypoxic MSC CM in the presence of IL-4 and collected cells for scRNA-seq analyses. Bioinformatic analyses confirmed multiple macrophage subpopulations. We first performed comparative analyses between macrophages cultured in hypoxic and normoxic MSC CM. Integration of these data sets showed large overlap between macrophage subsets; however, we identified a unique hypoxic MSC CM-induced macrophage cluster. Gene Ontogeny (GO) analyses revealed enrichment in IL-10, Ccl5/Ccr5, G alpha (i) Signaling, and Rho GTPases within this unique cluster. To determine if factors from MSC CM simulated effects of the anti-inflammatory cytokine IL-4, we integrated the data from macrophages cultured in hypoxic MSC CM with and without IL-4 addition. Integration of these data sets showed considerable overlap, demonstrating that hypoxic MSC CM simulates the effects of IL-4. Interestingly, macrophages cultured in normoxic MSC CM in the absence of IL-4 did not significantly contribute to the unique cluster within our comparison analyses and showed differential TGF-β signaling; thus, normoxic conditions did not approximate IL-4. In addition, TGF-β neutralization partially limited the effects of MSC CM. Our study identifies a unique macrophage subset induced by MSCs within hypoxic conditions, and supports that MSCs alter macrophage phenotypes through TGF-β-dependent mechanisms

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PDLSC-CM targets HAPLN1 in macrophages to reduce root resorption in delayed replanted teeth

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