Macrophages play a key role in wound healing.Dysfunction of their MO polarization to M2 leads to disorders of the wound immune microenvironment and chronic inflammation,which affects wound healing.Regulating the polar...Macrophages play a key role in wound healing.Dysfunction of their MO polarization to M2 leads to disorders of the wound immune microenvironment and chronic inflammation,which affects wound healing.Regulating the polarization of Mo macrophages to M2 macro-phages is an effective strategy for treating wound healing.Mesenchymal stem cells(MsCs)deliver endogenous regulatory factors via paracrine extracellular vesicles,which may play a key role in wound healing,and previous studies have shown that apoptotic bodies(ABs)are closely associated with inflammation regression and macrophage polarization.However,the specific regulatory mechanisms involved in ABs remain unknown.In the present study,we de-signed an MSC-AB(MSC-derived AB)-loaded polycaprolactone(PCL)scaffold,evaluated the macrophage phenotype and skin wound inflammation in vivo and in vitro,and explored the ability of MSC-AB-loaded PCL scaffolds to promote wound healing.Our data suggest that the PCL scaffold regulates the expression of the CCL-1 gene by targeting the delivery of mmu-miR-21a-5p by local sustained-release MSC-ABs,and drives MO macrophages to program M2 macrophages to regulate inflammation and angiogenesis,thereby synergistically promoting wound healing.This study provides a promising therapeutic strategy and experimental basis for treating various diseases associated with imbalances in proinflammatory and anti-inflammatory immuneresponses.展开更多
Bone morphogenetic protein 9(BMP9)exhibits remarkable osteogenic potential.However,the intricate mechanisms driving this function of BMP9 remain elusive.This study en-deavors to investigate the potential role of sirtu...Bone morphogenetic protein 9(BMP9)exhibits remarkable osteogenic potential.However,the intricate mechanisms driving this function of BMP9 remain elusive.This study en-deavors to investigate the potential role of sirtuin 5(SIRT5)in enhancing BMP9’s osteogenic capacity and decipher the underlying molecular pathways.To achieve this aim,we employed real-time PCR,western blotting,histochemical staining,and a cranial defect repair model to assess the impact of SIRT5 on BMP9-mediated osteogenesis.We utilized real-time PCR,western blotting,immunofluorescent staining,and immunoprecipitation assay to explore the associated mechanisms.Our results revealed that SIRT5 significantly up-regulated BMP9-induced osteogenic markers,while SIRT5 knockdown reduced their expression.Concurrently,hypoxia-inducible factor 1 subunit alpha(HIF-1a)level was increased by SIRT5,but reduced by SIRT5 knockdown.Notably,HIF-1a potentiated the SIRT5’s ability to strengthen BMP9’s osteogenic potential,whereas HIF-1a silencing reduced this effect,which was confirmed by bone defect repair assay.The acetylation and malonylation levels of HIF-1a were reduced by SIRT5,which may enhance its stability to promote BMP9’s osteogenic effect.Conversely,SIRT5 knockdown reversed these effects and promoted the degradation of HIF-1a.Collectively,our results demonstrated that the BMP9’s osteogenic potential could be promoted by SIRT5,potentially through stabilizing HIF-1a by reducing its acetylation and malonylation modifica-tion.This discovery may offer a novel strategy to accelerate bone tissue engineering by enhancing osteogenic differentiation,and it also sheds light on the possible mechanisms un-derlying BMP9-mediated osteogenic differentiation.展开更多
基金supported by the National Natural Science Foundation of China (No.82072443,82372425)the Chongqing Outstanding Project of Overseas Chinese Entrepreneurship and Innovation Support Program (China) (No.CX2022032)+6 种基金the Articular Cartilage Tissue Engineering and Regenerative Medicine Team,Chongqing Medical University (No.W0080)the General Project of Natural Science Foundation of Chongqing,China (No.CSTB2023NSCQMSX0166)the"Tomorrow Cup"Teacher-Student Cocreation Teaching and Research Innovation Project of International Medical College of Chongqing Medical University (No.KY20220204)the Chengdu Medical Research Project (Sichuan,China) (No.2023191)the China Postdoctoral Science Foundation (No.2022M710557)the Natural Science Foundation of Chongqing,China (No.CSTB2023NSCQBHx0011)the Young Excellent Science and Technology Talent Project of the First Affiliated Hospital of Chongqing Medical University (No.ZYRC2022-05).
文摘Macrophages play a key role in wound healing.Dysfunction of their MO polarization to M2 leads to disorders of the wound immune microenvironment and chronic inflammation,which affects wound healing.Regulating the polarization of Mo macrophages to M2 macro-phages is an effective strategy for treating wound healing.Mesenchymal stem cells(MsCs)deliver endogenous regulatory factors via paracrine extracellular vesicles,which may play a key role in wound healing,and previous studies have shown that apoptotic bodies(ABs)are closely associated with inflammation regression and macrophage polarization.However,the specific regulatory mechanisms involved in ABs remain unknown.In the present study,we de-signed an MSC-AB(MSC-derived AB)-loaded polycaprolactone(PCL)scaffold,evaluated the macrophage phenotype and skin wound inflammation in vivo and in vitro,and explored the ability of MSC-AB-loaded PCL scaffolds to promote wound healing.Our data suggest that the PCL scaffold regulates the expression of the CCL-1 gene by targeting the delivery of mmu-miR-21a-5p by local sustained-release MSC-ABs,and drives MO macrophages to program M2 macrophages to regulate inflammation and angiogenesis,thereby synergistically promoting wound healing.This study provides a promising therapeutic strategy and experimental basis for treating various diseases associated with imbalances in proinflammatory and anti-inflammatory immuneresponses.
基金supported by the Chongqing Medical University Program for Youth Innovation in Future Medicine(No.W0154 to B.C.H.and J.Y.L.)Chongqing Science and Technology Bureau(China)(No.CSTB2024NSCQ-MSX0411 to B.C.H.).
文摘Bone morphogenetic protein 9(BMP9)exhibits remarkable osteogenic potential.However,the intricate mechanisms driving this function of BMP9 remain elusive.This study en-deavors to investigate the potential role of sirtuin 5(SIRT5)in enhancing BMP9’s osteogenic capacity and decipher the underlying molecular pathways.To achieve this aim,we employed real-time PCR,western blotting,histochemical staining,and a cranial defect repair model to assess the impact of SIRT5 on BMP9-mediated osteogenesis.We utilized real-time PCR,western blotting,immunofluorescent staining,and immunoprecipitation assay to explore the associated mechanisms.Our results revealed that SIRT5 significantly up-regulated BMP9-induced osteogenic markers,while SIRT5 knockdown reduced their expression.Concurrently,hypoxia-inducible factor 1 subunit alpha(HIF-1a)level was increased by SIRT5,but reduced by SIRT5 knockdown.Notably,HIF-1a potentiated the SIRT5’s ability to strengthen BMP9’s osteogenic potential,whereas HIF-1a silencing reduced this effect,which was confirmed by bone defect repair assay.The acetylation and malonylation levels of HIF-1a were reduced by SIRT5,which may enhance its stability to promote BMP9’s osteogenic effect.Conversely,SIRT5 knockdown reversed these effects and promoted the degradation of HIF-1a.Collectively,our results demonstrated that the BMP9’s osteogenic potential could be promoted by SIRT5,potentially through stabilizing HIF-1a by reducing its acetylation and malonylation modifica-tion.This discovery may offer a novel strategy to accelerate bone tissue engineering by enhancing osteogenic differentiation,and it also sheds light on the possible mechanisms un-derlying BMP9-mediated osteogenic differentiation.
