The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration

The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury-repair process following lung injury.Pulmonary fibrosis(PF)is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells.In this study,we report that P21 expression was increased in alveolar epithelial type 2 cells(AEC2 s)in a time-dependent manner following multiple bleomycin-induced PF.Repeated injury of AEC2 s resulted in telomere shortening and triggered P21-dependent cell senescence.AEC2 s with elevated expression of P21 lost their self-renewal and differentiation abilities.In particular,elevated P21 not only induced cell cycle arrest in AEC2 s but also bound to P300 andβ-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction.Meanwhile,senescent AEC2 s triggered myofibroblast activation by releasing profibrotic cytokines.Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF.The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development,which suggests a potential strategy for the treatment of fibrotic lung diseases.

Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells promote alveolar bone regeneration by regulating macrophage polarization

Alveolar bone regeneration has been strongly linked to macrophage polarization.M1 macrophages aggravate alveolar bone loss,whereas M2 macrophages reverse this process.Berberine(BBR),a natural alkaloid isolated and refined from Chinese medicinal plants,has shown therapeutic effects in treating metabolic disorders.In this study,we first discovered that culture supernatant(CS)collected from BBR-treated human bone marrow mesenchymal stem cells(HBMSCs)ameliorated periodontal alveolar bone loss.CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro.To clarify the underlying mechanism,the bioactive materials were applied to different animal models.We discovered macrophage colony-stimulating factor(M-CSF),which regulates macrophage polarization and promotes bone formation,a key macromolecule in the CS.Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats.Colony-stimulating factor 1 receptor(CSF1R)inhibitor or anti-human M-CSF(M-CSF neutralizing antibody,Nab)abolished the therapeutic effects of the CS of BBR-treated HBMSCs.Moreover,AKT phosphorylation in macrophages was activated by the CS,and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab.These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis.Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets.Overall,our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.

An injectable and coagulation-independent Tetra-PEG hydrogel bioadhesive for post-extraction hemostasis and alveolar bone regeneration

Effective control of post-extraction hemorrhage and alveolar bone resorption is critical for successful extraction socket treatment,which remains an unmet clinical challenge.Herein,an injectable Tetra-PEG hydrogel that possesses rapid gelation,firm tissue adhesion,high mechanical strength,suitable degradability,and excellent biocompatibility is developed as a sutureless and coagulation-independent bioadhesive for the management of extraction sockets.Our results demonstrate that the rapid and robust adhesive sealing of the extraction socket by the Tetra-PEG hydrogel can provide reliable protection for the underlying wound and stabilize blood clots to facilitate tissue healing.In vivo experiments using an anticoagulated rat tooth extraction model show that the hydrogel significantly outperformed clinically used cotton and gelatin sponge in hemostatic efficacy,wound closure,alveolar ridge preservation,and in situ alveolar bone regeneration.Histomorphological evaluations reveal the mechanisms for accelerated bone repair through suppressed long-term inflammation,elevated collagen deposition,higher osteoblast activity,and enhanced angiogenesis.Together,our study highlights the clinical potential of the developed injectable Tetra-PEG hydrogel for treating anticoagulant-related post-extraction hemorrhage and improving socket healing.

An anti-bacterial porous shape memory self-adaptive stiffened polymer for alveolar bone regeneration after tooth extraction

The regeneration of alveolar bone after tooth extraction is critical for the placement of dental implants.Developing a rigid porous scaffold with defect shape adaptability is of great importance but challenging for alveolar bone regeneration.Herein,we design and synthesize a biocompatible poly(L-glutamic acid)-g-poly(ε-caprolactone)(PLGA-g-PCL)porous shape memory(SM)polymer.The PLGA-g-PCL is then copolymerized with acryloyl chloride grafted poly(ω-pentadecalactone)(PPDLDA)having a higher phase transition temperature than shape recovery temperature to maintain stiffness after shape recovery to resist chewing force.The hybrid pol-ydopamine/silver/hydroxyapatite(PDA/Ag/HA)is coated to the surface of(PLGA-g-PCL)-PPDL scaffold to afford the anti-bacterial activity.The porous SM scaffold can be deformed into a compact size and administered into the socket cavity in a minimally invasive mode,and recover its original shape with a high stiffness at body tem-perature,fitting well in the socket defect.The SM scaffold exhibits robust antibacterial activity against Staphy-lococcus aureus(S.aureus).The porous microstructure and cytocompatibility of PLGA allow for the ingrowth and proliferation of stem cells,thus facilitating osteogenic differentiation.The micro-CT and histological analyses demonstrate that the scaffold boosts efficient new bone regeneration in the socket of rabbit mandibular first premolar.This porous shape memory self-adaptive stiffened polymer opens up a new avenue for alveolar bone regeneration.

A five-in-one novel MOF-modified injectable hydrogel with thermo-sensitive and adhesive properties for promoting alveolar bone repair in periodontitis:Antibacterial,hemostasis,immune reprogramming,pro-osteo-/angiogenesis and recruitment

Periodontitis is a chronic inflammatory disease caused by plaque that destroys the alveolar bone tissues,resulting in tooth loss.Poor eradication of pathogenic microorganisms,persistent malignant inflammation and impaired osteo-/angiogenesis are currently the primary challenges to control disease progression and rebuild damaged alveolar bone.However,existing treatments for periodontitis fail to comprehensively address these issues.Herein,an injectable composite hydrogel(SFD/CS/ZIF-8@QCT)encapsulating quercetin-modified zeolitic imidazolate framework-8(ZIF-8@QCT)is developed.This hydrogel possesses thermo-sensitive and adhesive properties,which can provide excellent flowability and post-injection stability,resist oral fluid washout as well as achieve effective tissue adhesion.Inspirationally,it is observed that SFD/CS/ZIF-8@QCT exhibits a rapid localized hemostatic effect following implantation,and then by virtue of the sustained release of zinc ions and quercetin exerts excellent collective functions including antibacterial,immunomodulation,pro-osteo-/angiogenesis and pro-recruitment,ultimately facilitating excellent alveolar bone regeneration.Notably,our study also demonstrates that the inhibition of osteo-/angiogenesis of PDLSCs under the periodontitis is due to the strong inhibition of energy metabolism as well as the powerful activation of oxidative stress and autophagy,whereas the synergistic effects of quercetin and zinc ions released by SFD/CS/ZIF-8@QCT are effective in reversing these biological processes.Overall,our study presents innovative insights into the advancement of biomaterials to regenerate alveolar bone in periodontitis.