Abstract
Periodontal disease may cause considerable destruction of alveolar bone, periodontal ligaments (PDLs) and cementum and even lead to progressive oral dysfunction. Periodontal tissue regeneration is the ultimate goal of periodontal disease treatment to reconstruct both structures and functions. However, the regenerative efficiency is low, possibly due to the lack of a proper periodontal microenvironment. In this study, we applied an injectable and thermosensitive chitosan/gelatin/glycerol phosphate hydrogel to provide a 3D environment for transplanted stem cells and to enhance stem cell delivery and engraftment. The iPSCs-BMP-6-hydrogel complex promoted osteogenesis and the differentiation of new connective tissue and PDL formation. In animal models of maxillary-molar defects, the iPSCs-BMP-6-hydrogel-treated group showed significant mineralization with increased bone volume, trabecular number and trabecular thickness. Synergistic effects of iPSCs and BMP-6 increased both bone and cementum formation. IPSCs-BMP-6-hydrogel-treated animals showed new bone synthesis (increased ALP- and TRAP-positive cells), new PDL regeneration (shown through Masson’s trichrome staining and a qualification assay), and reduced levels of inflammatory cytokines. These findings suggest that hydrogel-encapsulated iPSCs combined with BMP-6 provide a new strategy to enhance periodontal regeneration. This combination not only promoted stem cell-derived graft engraftment but also minimized the progress of inflammation, which resulted in highly possible periodontal regeneration.
Highlights
Evaluation of pluripotency from Induced pluripotent stem cells (iPSCs). iPSCs are an alternative source of pluripotent cells that avoid the ethical issues arose in the field of tissue regeneration, and the generation procedure for these cells has been standardized and well established[17]
We evaluated the pluripotency of iPSCs by measuring embryonic bodies (EBs) formation and three germ layer differentiation
We addressed the potential regulatory circuit within periodontal regeneration and osteogenesis which were generated through the use of IPA (QIAGEN Inc., https://www.qiagenbioinformatics. com/products/ingenuity-pathway-analysis)[18], and found that Bone morphogenetic proteins (BMPs)-6 was closely linked to several markers and effectors involved in bone formation
Summary
The aims of this study focused on constructing a 3D-periodontal therapeutic environment system that combined iPSCs therapy with hydrogel-BMP6 to reprogram the periodontal defects and remodel periodontal regeneration in vivo. To this end, we developed a BMP-6 sustaining releasing system with thermosensitive hydrogel that served as a 3D bio-scaffold for iPSCs to be engrafted and induced into a lineage of periodontal tissues. We validated the capabilities and advantages of using iPSCs combined with BMP-6 in periodontal tissue regeneration in this study, and we further demonstrated the effects of the iPSCs-BMP-6-hydrogel combination in 3D culture as a regenerative biomaterial for periodontal functional repair both in vitro and in vivo
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