Due to the unique microstructures and components of extracellular matrix(ECM),decellularized scaffolds had been used widely in clinical.The reaction of the host toward decellularized scaffolds depends on their biocomp...Due to the unique microstructures and components of extracellular matrix(ECM),decellularized scaffolds had been used widely in clinical.The reaction of the host toward decellularized scaffolds depends on their biocompatibility,which should be satisfied before applied in clinical.The aim of this study is to develop a decellularized xenograft material with good biocompatibility for further bone repair,in an effective and gentle method.The existing chemical and physical decellularization techniques including ethylene diamine tetraacetic acid(EDTA),sodium dodecyl sulfate(SDS)and supercritical carbon dioxide(SC-CO2)were combined and modified to decellularize bovine cancellous bone(CB).After decellularization,almost 100%of A-Gal epitopes were removed,the combination of collagen,calcium and phosphate was reserved.The direct and indirect contact with macrophages was used to evaluate the cytotoxicity and immunological response of the materials.Mesenchymal stem cells(MSCs)were used in the in vitro cells’proliferation assay.The decellularized CB was proved has no cytotoxicity(grade 1)and no immunological response(NO,IL-2,IL-6 and TNF-α secretion inhibited),and could support MSCs proliferated continuedly.These results were similar to that of commercial decellularized human bone.This study suggests the potential of using this kind of combine decellularization process to fabricate heterogeneous ECM scaffolds for clinical application.展开更多
Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma(HCC)are urgently needed.The common cytokine receptorγchain(γc)family cytokines such as IL-2,IL-7,IL-15 and IL-21 play fu...Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma(HCC)are urgently needed.The common cytokine receptorγchain(γc)family cytokines such as IL-2,IL-7,IL-15 and IL-21 play fundamental roles in T cell development,differentiation and effector phases.This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy.The antitumor function of AFP-specific T cell receptor-engineered T cells(TCR-T)was augmented by exogenous IL-21 in vitro and in vivo.IL-21 enhanced proliferation capacity,promoted memory differentiation,downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation.A novel engineered IL-21 receptor was established,and TCR-T armed with the novel engineered IL-21 receptors(IL-21R-TCR-T)showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand.IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo.IL-21R-TCR-T exhibited a less differentiated,exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation.The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization.The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.展开更多
基金supported by National Natural Science Foundation of China(51502094)Special Fund Project for Guangdong Academy of Sciences to Build First-Class Research Institutions in China(2020GDASYL-20200103038)+4 种基金National Key R&D Plans(2018YFC1105902)China Postdoctoral Science Foundation(2017M612657)Guangdong Province Science and Technology Projects(2013B021800137)Pearl River Nova Program of Guangzhou(201610010168)Guangdong Province Medical Research Foundation(A2016060).
文摘Due to the unique microstructures and components of extracellular matrix(ECM),decellularized scaffolds had been used widely in clinical.The reaction of the host toward decellularized scaffolds depends on their biocompatibility,which should be satisfied before applied in clinical.The aim of this study is to develop a decellularized xenograft material with good biocompatibility for further bone repair,in an effective and gentle method.The existing chemical and physical decellularization techniques including ethylene diamine tetraacetic acid(EDTA),sodium dodecyl sulfate(SDS)and supercritical carbon dioxide(SC-CO2)were combined and modified to decellularize bovine cancellous bone(CB).After decellularization,almost 100%of A-Gal epitopes were removed,the combination of collagen,calcium and phosphate was reserved.The direct and indirect contact with macrophages was used to evaluate the cytotoxicity and immunological response of the materials.Mesenchymal stem cells(MSCs)were used in the in vitro cells’proliferation assay.The decellularized CB was proved has no cytotoxicity(grade 1)and no immunological response(NO,IL-2,IL-6 and TNF-α secretion inhibited),and could support MSCs proliferated continuedly.These results were similar to that of commercial decellularized human bone.This study suggests the potential of using this kind of combine decellularization process to fabricate heterogeneous ECM scaffolds for clinical application.
基金The study was sponsored by the National Key Research and Development Program of China(No.2022YFC2303600)the National Natural Science Foundation of China(82073360 and 81802449)+1 种基金the Guangdong Basic and Applied Basic Research Foundation(2023A1515012169,2021A1515220100,2020A1515011313)the Outstanding Youth Development Scheme of Nanfang Hospital,Southern Medical University(2020J004).
文摘Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma(HCC)are urgently needed.The common cytokine receptorγchain(γc)family cytokines such as IL-2,IL-7,IL-15 and IL-21 play fundamental roles in T cell development,differentiation and effector phases.This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy.The antitumor function of AFP-specific T cell receptor-engineered T cells(TCR-T)was augmented by exogenous IL-21 in vitro and in vivo.IL-21 enhanced proliferation capacity,promoted memory differentiation,downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation.A novel engineered IL-21 receptor was established,and TCR-T armed with the novel engineered IL-21 receptors(IL-21R-TCR-T)showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand.IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo.IL-21R-TCR-T exhibited a less differentiated,exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation.The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization.The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.