6-Bromoindirubin-3′-oxime Promotes Osteogenic Differentiation of Periodontal Ligament Stem Cells and Facilitates Bone Regeneration in a Mouse Periodontitis Model

Abstract

Effective bone tissue engineering is important to overcome the unmet clinical challenges of periodontal tissue regeneration. Successful bone tissue engineering comprises three key factors: stem cells, growth factors, and scaffolds. 6-Bromoindirubin-3′-oxime (BIO) is an inhibitor of glycogen synthase kinase-3 (GSK-3) that can activate the Wnt signaling pathway by enhancing β-catenin activity. In this study, the effects of BIO on the proliferation, migration, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs) were investigated. Poly­(lactic-co-glycolic acid) (PLGA) and hyaluronic acid (HA) emerged as promising biomaterials; thus, we developed a novel HA hydrogel embedded with BIO-encapsulated PLGA microspheres and injected the formulation into the gingival sulcus of mice with experimental periodontitis. The release speed of this system was fast in the first week and followed a sustained release phase until week 4. In vivo experiments showed that this PLGA-BIO–HA hydrogel system can inhibit periodontal inflammation, promote bone regeneration, and induce the expression of bone-forming markers alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and osteocalcin (OCN) in a mouse periodontitis model. Therefore, this PLGA-BIO–HA hydrogel system provides a promising therapeutic strategy for periodontal bone regeneration.

6-Bromoindirubin-3′-Oxime Regulates Colony Formation, Apoptosis, and Odonto/Osteogenic Differentiation in Human Dental Pulp Stem Cells

“…In the present study, BIO treatment enhanced hDPSC osteogenic differentiation, as seen by increased ALP activity, odonto/osteogenic marker gene expression, and mineralised nodule formation. Similar results were found in other cell types, e.g., human PDLSCs [ 59 ], mouse PDLSCs [ 60 ], apical papilla stem cells [ 61 ], mouse DPs [ 62 ], hBMSCs [ 38 ], canine BMSCs [ 46 ], and mouse embryonic fibroblasts [ 63 ]. In contrast, it has been reported that LiCl-mediated Wnt signaling activation decreased the osteogenic differentiation [ 64 , 65 ].…”

Hydrogels for the treatment of oral and maxillofacial diseases: current research, challenges, and future directions

“…In recent study, 6-Bromoindirubin-3'-oxime (BIO) was encapsulated into PLGA microspheres and loaded on HA hydrogel. Injected into the gingival sulcus of mice with experimental periodontitis, the PLGA-HA hydrogel system could release BIO via free diffusion and promote osteogenesis process 146 . Other studies demonstrated similar results associated with hydrogels incorporating SDF-1, BMP-2, NapFFY 147 .…”

Advances of Hydrogel Therapy in Periodontal Regeneration—A Materials Perspective Review

“…The incorporation of PVA and natural polymers significantly compensated for the poor mechanical properties of natural polymer-based hydrogels and remained favorable for cytocompatibility and bioactivity [ 63 , 64 ]. PLGA is a non-toxic, degradable polymeric organic compound made by the polymerization of lactic acid and hydroxyacetic acid which has high biocompatibility and capsule- and film-forming properties as a carrier for cell implantation [ 65 ].…”