Due to increasing morbidity worldwide,fractures are becoming an emerging public health concern.This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures.Type H ...Due to increasing morbidity worldwide,fractures are becoming an emerging public health concern.This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures.Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis.Here,we show that metformin accelerated fracture healing in both osteoporotic and normal mice.Moreover,metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing.Mechanistically,metformin increased the expression of HIF-1α,an important positive regulator of type H vessel formation,by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells(HMECs).The results of HIF-1αor YAP1/TAZ interference in hypoxia-cultured HMECs using si RNA further suggested that the enhancement of HIF-1αand its target genes by metformin is primarily through YAP1/TAZ inhibition.Finally,overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair.In summary,our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.展开更多
Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extrace...Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.展开更多
基金supported by the National Natural Science Foundation of China (Grant Nos.81874006,82172399,81902222,82060395,81902277,82072504,82000845)the Hunan Province Natural Science Foundation of China (Grant Nos.2020JJ4928,2020JJ4897,2021JJ30038,2021JJ40492)the Independent Exploration and Innovation Project of Central South University (Grant Nos.2020zzts255)。
文摘Due to increasing morbidity worldwide,fractures are becoming an emerging public health concern.This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures.Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis.Here,we show that metformin accelerated fracture healing in both osteoporotic and normal mice.Moreover,metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing.Mechanistically,metformin increased the expression of HIF-1α,an important positive regulator of type H vessel formation,by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells(HMECs).The results of HIF-1αor YAP1/TAZ interference in hypoxia-cultured HMECs using si RNA further suggested that the enhancement of HIF-1αand its target genes by metformin is primarily through YAP1/TAZ inhibition.Finally,overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair.In summary,our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.
基金supported by the National Natural Science Foundation of China(Grant Nos.82125023,82072504,81871822,82172501,81801395,and 82200039)the Science and Technology Innovation Program of Hunan Province(Grant Nos.2020RC4008 and 2022RC1211,China)+4 种基金the China National Postdoctoral Program for Innovative Talents(Grant No.BX2021383,China)the Central South University InnovationDriven Research Programme(Grant Nos.2023CXQD001 and 2019CX014,China)the Hunan Province Natural Science Foundation of China(Grant Nos.2023JJ10094 and 2020JJ5883)the Youth Science Foundation of Xiangya Hospital(Grant No.2022Q07,China)the Hunan Provincial Innovation Foundation for Postgraduate(Grant Nos.2021ZZTS0342 and 2022ZZTS0239,China)。
文摘Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.
