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Extracellular vesicles (EVs) are future promising therapeutics, but their instability in vivo after administration remains an important barrier to their further development. Many groups evaluated EV surface modification strategies to add a targeting group with the aim of controlling EV biodistribution. Conversely, fewer groups focused on their stabilization to obtain "stealth" allogenic EVs. Modulating their stabilization and biodistribution is an essential prerequisite for their development as nano-therapeutics. Here, we explored polyoxazolines with lipid anchors association to the EV membrane (POxylation as an alternative to PEGylation) to stabilize EVs in plasma and control their biodistribution, while preserving their native properties. We found that this modification maintained and seemed to potentiate the immunomodulatory properties of EVs derived from mesenchymal stem/stromal cells (MSC). Using a radiolabeling protocol to track EVs at a therapeutically relevant concentration in vivo, we demonstrated that POxylation is a promising option to stabilize EVs in plasma because it increased EV half-life by 6 fold at 6 h post-injection. Moreover, EV accumulation in tumors was higher after POxylation than after PEGylation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Morille reports financial support was provided by French National Research Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Initially discovered for its ability to regenerate ear holes, the Murphy Roth Large (MRL) mouse has been the subject of multiple research studies aimed at evaluating its ability to regenerate other body tissues and at deciphering the mechanisms underlying it. These enhanced abilities to regenerate, retained during adulthood, protect the MRL mouse from degenerative diseases such as osteoarthritis (OA). Here, we hypothesized that mesenchymal stromal/stem cells (MSC) derived from the regenerative MRL mouse could be involved in their regenerative potential through the release of pro-regenerative mediators., Method: To address this hypothesis, we compared the secretome of MRL and BL6 MSC and identified several candidate molecules expressed at significantly higher levels by MRL MSC than by BL6 MSC. We selected one candidate, Plod2, and performed functional in vitro assays to evaluate its role on MRL MSC properties including metabolic profile, migration, and chondroprotective effects. To assess its contribution to MRL protection against OA, we used an experimental model for osteoarthritis induced by collagenase (CiOA)., Results: Among the candidate molecules highly expressed by MRL MSC, we focused our attention on procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2). Plod2 silencing induced a decrease in the glycolytic function of MRL MSC, resulting in the alteration of their migratory and chondroprotective abilities in vitro. In vivo, we showed that Plod2 silencing in MRL MSC significantly impaired their capacity to protect mouse from developing OA., Conclusion: Our results demonstrate that the chondroprotective and therapeutic properties of MRL MSC in the CiOA experimental model are in part mediated by PLOD2., (© 2024. The Author(s).)

Osteoarthritis (OA), the most common degenerative and inflammatory joint disorder, is multifaceted. Indeed, OA characteristics include cartilage degradation, osteophytes formation, subchondral bone changes, and synovium inflammation. The difficulty in discovering new efficient treatments for OA patients up to now comes from the adoption of monotherapy approaches targeting either joint tissue repair/catabolism or inflammation to address the diverse components of OA. When satisfactory, these approaches only provide short-term beneficial effects, since they only result in the repair and not the full structural and functional reconstitution of the damaged tissues. In the present review, we will briefly discuss the current therapeutic approaches used to repair the damaged OA cartilage. We will highlight the results obtained with cell-based products in clinical trials and demonstrate how the current strategies result in articular cartilage repair showing restricted early-stage clinical improvements. In order to identify novel therapeutic targets and provide to OA patients long-term clinical benefits, herein, we will review the basis of the regenerative process. We will focus on macrophages and their ambivalent roles in OA development and tissue regeneration, and review the therapeutic strategies to target the macrophage response and favor regeneration in OA., Competing Interests: CT-A and MW were employed by CellVax. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bohaud, Contreras-Lopez, De La Cruz, Terraza-Aguirre, Wei, Djouad and Jorgensen.)

Objectives: To explore the macrophage profiles in symptomatic and asymptomatic forms of AP through phenotypic and functional analyses., Material and Methods: Cross-sectional study. Apical tissue/lesion samples were collected from patients with clinical diagnosis of AAP (n = 51) or SAP (n = 45) and healthy periodontal ligament (HPL) from healthy patients as controls (n = 14), all with indication of tooth extraction. Samples were digested, cells were stained for CD14, M1 (CD64, CD80), and M2 (CD163, CD206) phenotypic surface markers and analyzed by flow cytometry. Functional cytokine profiles L-6, IL-12, TNF-α, IL-23 (M1), IL-10, and TGF-β (M2) were determined by qPCR., Results: Higher macrophage M1/M2 ratio (CD64 + CD80 + /CD163 + CD206 + ) along with lower CD163 mean fluorescence intensity (MFI) were found in SAP compared to AAP and controls (p < 0.05). IL-6, IL-12, TNF-α, IL-23 (M1), and IL-10 mRNA (M2) were upregulated, whereas TGF-β mRNA (M2) was downregulated in apical lesions compared to controls. Specifically, IL-6 and IL-23 (M1) were upregulated in SAP compared with AAP and controls (p < 0.05). The data were analyzed with Kruskal-Wallis test., Conclusions: Macrophages exhibited a polarization switch towards M1 in AL. SAP exhibited a reduced M2 differentiation profile based on a reduction of CD163 expression levels in SAP over AAP. Specifically, IL-6 and IL-23 were augmented SAP over AAP, suggesting a role in the severity of apical lesions., Clinical Relevance: Deciphering the macrophage polarization and functions in apical periodontitis can contribute to explain AP dynamics, its clinical presentation and systemic impact.

Aggregatibacter actinomycetemcomitans is a Gram-negative oral bacterium with high immunostimulatory and pathogenic potential involved in the onset and progression of periodontitis, a chronic disease characterized by aberrant immune responses followed by tooth-supporting bone resorption, which eventually leads to tooth loss. While several studies have provided evidence related to the virulence factors of A. actinomycetemcomitans involved in the host cell death and immune evasion, such as its most studied primate-specific virulence factor, leukotoxin, the role of specific lipopolysaccharide (LPS) domains remain poorly understood. Here, we analyzed the role of the immunodominant domain of the LPS of A. actinomycetemcomitans termed O-polysaccharide (O-PS), which differentiates the distinct bacterial serotypes based on its antigenicity. To determine the role of the O-PS in the immunogenicity and virulence of A. actinomycetemcomitans during periodontitis, we analyzed the in vivo and in vitro effect of an O-PS-defective transposon mutant serotype b strain, characterized by the deletion of the rmlC gene encoding the α-L-rhamnose sugar biosynthetic enzyme. Induction of experimental periodontitis using the O-PS-defective rmlC mutant strain resulted in lower tooth-supporting bone resorption, infiltration of Th1, Th17, and Th22 lymphocytes, and expression of Ahr , Il1b , Il17 , Il23 , Tlr4 , and RANKL ( Tnfsf11 ) in the periodontal lesions as compared with the wild-type A. actinomycetemcomitans strain. In addition, the O-PS-defective rmlC mutant strain led to impaired activation of antigen-presenting cells, with less expression of the co-stimulatory molecules CD40 and CD80 in B lymphocytes and dendritic cells, and downregulated expression of Tnfa and Il1b in splenocytes. In conclusion, these data demonstrate that the O-PS from the serotype b of A. actinomycetemcomitans plays a key role in the capacity of the bacterium to prime oral innate and adaptive immune responses, by triggering the Th1 and Th17-driven tooth-supporting bone resorption during periodontitis., (Copyright © 2020 Monasterio, Castillo, Astorga, Hoare, Terraza-Aguirre, Cafferata, Villablanca and Vernal.)

Mesenchymal stem cells (MSCs) exhibit potent immunoregulatory abilities by interacting with cells of the adaptive and innate immune system. In vitro, MSCs inhibit the differentiation of T cells into T helper 17 (Th17) cells and repress their proliferation. In vivo, the administration of MSCs to treat various experimental inflammatory and autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and bowel disease showed promising therapeutic results. These therapeutic properties mediated by MSCs are associated with an attenuated immune response characterized by a reduced frequency of Th17 cells and the generation of regulatory T cells. In this manuscript, we review how MSC and Th17 cells interact, communicate, and exchange information through different ways such as cell-to-cell contact, secretion of soluble factors, and organelle transfer. Moreover, we discuss the consequences of this dynamic dialogue between MSC and Th17 well described by their phenotypic and functional plasticity.

Aim: T lymphocytes play a central role during the pathogenesis of periodontitis, and the imbalance between the pathogenic T-helper type 17 (Th17) and protective T-regulatory (Treg) lymphocytes determines the tooth-supporting alveolar bone resorption. Interleukin (IL)-35 is a novel anti-inflammatory cytokine with therapeutic properties in diseases whose pathogenesis is associated with the Th17/Treg imbalance; however, its role during periodontitis has not been established yet. This study aimed to elucidate whether IL-35 inhibits the alveolar bone resorption during periodontitis by modulating the Th17/Treg imbalance., Materials and Methods: Mice with ligature-induced periodontitis were treated with locally or systemically administrated IL-35. As controls, periodontitis-affected mice without IL-35 treatment and non-ligated mice were used. Alveolar bone resorption was measured by micro-computed tomography and scanning electron microscopy. The Th17/Treg pattern of the immune response was analysed by qPCR, ELISA, and flow cytometry., Results: IL-35 inhibited alveolar bone resorption in periodontitis mice. Besides, IL-35 induced less detection of Th17 lymphocytes and production of Th17-related cytokines, together with higher detection of Treg lymphocytes and production of Treg-related cytokines in periodontitis-affected tissues., Conclusion: IL-35 is beneficial in the regulation of periodontitis; particularly, IL-35 inhibited alveolar bone resorption and this inhibition was closely associated with modulation of the periodontal Th17/Treg imbalance., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)