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Recruited CD68+CD206+ macrophages orchestrate graft immune tolerance to prompt xenogeneic-dentin matrix-based tooth root regeneration.


ABSTRACT: Successful regenerative medicine strategies of xenogeneic extracellular matrix need a synergistic balance among inflammation, fibrosis, and remodeling process. Adaptive macrophage subsets have been identified to modulate inflammation and orchestrate the repair of neighboring parenchymal tissues. This study fabricated PPAR?-primed CD68+CD206+ M2 phenotype (M2?), and firstly verified their anti-inflammatory and tissue-regenerating roles in xenogeneic bioengineered organ regeneration. Our results showed that Th1-type CD3+CD8+ T cell response to xenogeneic-dentin matrix-based bioengineered root complex (xeno-complex) was significantly inhibited by M2? macrophage in vitro. PPAR? activation also timely recruited CD68+CD206+ tissue macrophage polarization to xeno-complex in vivo. These subsets alleviated proinflammatory cytokines (TNF-?, IFN-?) at the inflammation site and decreased CD3+CD8+ T lymphocytes in the periphery system. When translated to an orthotopic nonhuman primate model, PPAR?-primed M2 macrophages immunosuppressed IL-1?, IL-6, TNF-?, MMPs to enable xeno-complex to effectively escape immune-mediated rejection and initiate graft-host synergistic integrity. These collective activities promoted the differentiation of odontoblast-like and periodontal-like cells to guide pulp-dentin and cementum-PDLs-bone regeneration and rescued partially injured odontogenesis such as DSPP and periostin expression. Finally, the regenerated root showed structure-biomechanical and functional equivalency to the native tooth. The timely conversion of M1-to-M2 macrophage mainly orchestrated odontogenesis, fibrogenesis, and osteogenesis, which represents a potential modulator for intact parenchymal-stromal tissue regeneration of targeted organs.

SUBMITTER: Li H 

PROVIDER: S-EPMC7567936 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Recruited CD68<sup>+</sup>CD206<sup>+</sup> macrophages orchestrate graft immune tolerance to prompt xenogeneic-dentin matrix-based tooth root regeneration.

Li Hui H   Sun Jingjing J   Yang Hefeng H   Han Xue X   Luo Xiangyou X   Liao LiJun L   Yang Bo B   Zhu Tian T   Huo Fangjun F   Guo Weihua W   Tian Weidong W  

Bioactive materials 20201014 4


Successful regenerative medicine strategies of xenogeneic extracellular matrix need a synergistic balance among inflammation, fibrosis, and remodeling process. Adaptive macrophage subsets have been identified to modulate inflammation and orchestrate the repair of neighboring parenchymal tissues. This study fabricated PPARγ-primed CD68<sup>+</sup>CD206<sup>+</sup> M2 phenotype (M2γ), and firstly verified their anti-inflammatory and tissue-regenerating roles in xenogeneic bioengineered organ regen  ...[more]

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