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...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+CD206+M2 phenotype(M2γ),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 M2γmacrophage in vitro.PPARγactivation also timely recruited CD68^(+)CD206^(+)tissue macrophage polarization to xeno-complex in vivo.These subsets alleviated proinflammatory cytokines(TNF-α,IFN-γ)at the inflammation site and decreased CD3^(+)CD8^(+)T lymphocytes in the periphery system.When translated to an orthotopic nonhuman primate model,PPARγ-primed M2 macrophages immunosuppressed IL-1β,IL-6,TNF-α,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.展开更多
基金This work was supported by the National Key Research and Development Program of China(Nos.2017YFA0104800),Nature Science Foundation of China(31771062,31971281,81901001),Key Research and Development Program of Sichuan Province(2017SZ0031).
文摘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+CD206+M2 phenotype(M2γ),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 M2γmacrophage in vitro.PPARγactivation also timely recruited CD68^(+)CD206^(+)tissue macrophage polarization to xeno-complex in vivo.These subsets alleviated proinflammatory cytokines(TNF-α,IFN-γ)at the inflammation site and decreased CD3^(+)CD8^(+)T lymphocytes in the periphery system.When translated to an orthotopic nonhuman primate model,PPARγ-primed M2 macrophages immunosuppressed IL-1β,IL-6,TNF-α,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.
