Vaccination is the preferred strategy for preventing infections such as influenza in elderly individuals;however,its efficacy is often suboptimal due in part to age-related declines in immune function.In this study,we...Vaccination is the preferred strategy for preventing infections such as influenza in elderly individuals;however,its efficacy is often suboptimal due in part to age-related declines in immune function.In this study,we discovered that the infusion of mesenchymal stromal cells(MSCs)restored defects in the splenic stromal cell network and lymphocyte architecture in aged mice while also increasing specific antibody levels following vaccine immunization.This significantly protected aging mice from influenza infection.Mechanistically,the delivered MSCs localized in the splenic marginal zones,where they positioned themselves near marginal reticular cells(MRCs)and stimulated MRC proliferation,partially through the action of vascular endothelial growth factor A(VEGFA).This MSC‒MRC interaction orchestrated the reconstruction of the stromal network,thereby restoring lymphocyte homeostasis and germinal center reactions.Importantly,the MSC-mediated enhancement of the vaccine response was further validated in aged cynomolgus monkeys.Collectively,our findings provide new insights into the application of MSCs in addressing age-related immune decline and highlight splenic MRCs as critical therapeutic targets.展开更多
Background and objective:Noninvasive non-alcoholic steatohepatitis(NASH)assessment is a clinical challenge to the management of non-alcoholic fatty liver disease.We aim to develop diagnostic models based on sequential...Background and objective:Noninvasive non-alcoholic steatohepatitis(NASH)assessment is a clinical challenge to the management of non-alcoholic fatty liver disease.We aim to develop diagnostic models based on sequential ultrasound molecular imaging(USMI)for the noninvasive identification of NASH in mouse models.Methods:Animal experiments were approved by the Animal Ethics Committee of South China Agricultural University.Forty-nine C57BL/6 mice were divided into normal control,non-alcoholic fatty liver,NASH,and hepatitis groups.Sequential USMI was implemented using CD36-targeted microbubbles(MBs-CD36)and intercellular adhesion molecule-1(ICAM-1)-targeted microbubbles(MBs-ICAM-1)to visualize hepatic steatosis and inflammation.The targeting signal of USMI was quantified as the normalized intensity difference(NID)with the destruction-replenishment method.Correlation analysis was conducted between the NID-MBs-CD36 and pathological steatosis score and between the NID-MBsICAM-1 and pathological inflammation score.Finally,diagnostic models combining NID-MBs-CD36 with NID-MBs-ICAM-1 were established for NASH diagnosis.Results:MBs-CD36 and MBs-ICAM-1 were successfully prepared and used for sequential USMI in all mice.NID-MBs-CD36 values increased with the progression of steatosis,while NID-MBs-ICAM-1 values increased in parallel with the progression of inflammation.A strong positive correlation was identified between NID-MBs-CD36 and pathological steatosis grade(r_(s)=0.9078,P<0.0001)and between NIDMBs-ICAM-1 and pathological inflammation grade(r_(s)=0.9071,P<0.0001).Among various sequential USMI-based diagnostic models,the serial testing model showed high diagnostic performance in detecting NASH,with 95%sensitivity,97%specificity,95%positive predictive values,97%negative predictive values,and 96%accuracy.Conclusions:Sequential USMI using MBs-CD36 and MBs-ICAM-1 allows noninvasive grading of hepatic steatosis and inflammation.Sequential USMI-based diagnostic models hold great potential in the noninvasive identification of NASH.展开更多
基金supported by grants from the National Key Research and Development Program of China,Stem Cell and Translational Research(2022YFA1104100,2022YFA1105000,2018YFA0801404)the National Natural Science Foundation of China(82570270,82270230,32130046,82171617,82471689,82170540,82471462,82270566)+8 种基金the Guangdong Basic and Applied Basic Research Foundation(2023B1515020119)the Key Research and Development Program of Guangdong Province(2023B1111050006)the Key Scientific and Technological Program of Guangzhou City(2023B01J1002,202206080002)the Pioneering Talents Project of the Guangzhou Development Zone(2021-L029)the Guangdong Special Support Program(2019BT02Y276)the Shenzhen Science and Technology Program(KJZD20230923114504008)the Sanming Project of Medicine in Shenzhen Nanshan(SZSM2021034008)the Science and Technology Planning Project of Gaozhou(20240619111622)the Special Funds for the Cultivation of Guangdong College Students'Scientific and Technological Innovation(pdjh2025ak003).
文摘Vaccination is the preferred strategy for preventing infections such as influenza in elderly individuals;however,its efficacy is often suboptimal due in part to age-related declines in immune function.In this study,we discovered that the infusion of mesenchymal stromal cells(MSCs)restored defects in the splenic stromal cell network and lymphocyte architecture in aged mice while also increasing specific antibody levels following vaccine immunization.This significantly protected aging mice from influenza infection.Mechanistically,the delivered MSCs localized in the splenic marginal zones,where they positioned themselves near marginal reticular cells(MRCs)and stimulated MRC proliferation,partially through the action of vascular endothelial growth factor A(VEGFA).This MSC‒MRC interaction orchestrated the reconstruction of the stromal network,thereby restoring lymphocyte homeostasis and germinal center reactions.Importantly,the MSC-mediated enhancement of the vaccine response was further validated in aged cynomolgus monkeys.Collectively,our findings provide new insights into the application of MSCs in addressing age-related immune decline and highlight splenic MRCs as critical therapeutic targets.
基金the Science and Technology Planning Project of Guangzhou,China(No.2023A03J0216)the National Natural Science Foundation of China(No.82272021)the Natural Science Foundation of Guangdong Province,China(No.2021A1515010635)and the Major Talents Programme of the Third Affiliated Hospital of Sun Yat-sen University(No.P02445).
文摘Background and objective:Noninvasive non-alcoholic steatohepatitis(NASH)assessment is a clinical challenge to the management of non-alcoholic fatty liver disease.We aim to develop diagnostic models based on sequential ultrasound molecular imaging(USMI)for the noninvasive identification of NASH in mouse models.Methods:Animal experiments were approved by the Animal Ethics Committee of South China Agricultural University.Forty-nine C57BL/6 mice were divided into normal control,non-alcoholic fatty liver,NASH,and hepatitis groups.Sequential USMI was implemented using CD36-targeted microbubbles(MBs-CD36)and intercellular adhesion molecule-1(ICAM-1)-targeted microbubbles(MBs-ICAM-1)to visualize hepatic steatosis and inflammation.The targeting signal of USMI was quantified as the normalized intensity difference(NID)with the destruction-replenishment method.Correlation analysis was conducted between the NID-MBs-CD36 and pathological steatosis score and between the NID-MBsICAM-1 and pathological inflammation score.Finally,diagnostic models combining NID-MBs-CD36 with NID-MBs-ICAM-1 were established for NASH diagnosis.Results:MBs-CD36 and MBs-ICAM-1 were successfully prepared and used for sequential USMI in all mice.NID-MBs-CD36 values increased with the progression of steatosis,while NID-MBs-ICAM-1 values increased in parallel with the progression of inflammation.A strong positive correlation was identified between NID-MBs-CD36 and pathological steatosis grade(r_(s)=0.9078,P<0.0001)and between NIDMBs-ICAM-1 and pathological inflammation grade(r_(s)=0.9071,P<0.0001).Among various sequential USMI-based diagnostic models,the serial testing model showed high diagnostic performance in detecting NASH,with 95%sensitivity,97%specificity,95%positive predictive values,97%negative predictive values,and 96%accuracy.Conclusions:Sequential USMI using MBs-CD36 and MBs-ICAM-1 allows noninvasive grading of hepatic steatosis and inflammation.Sequential USMI-based diagnostic models hold great potential in the noninvasive identification of NASH.
