Background:The protective effect of mesenchymal stem cells(MSCs)on cardiac ischemia-reperfusion(I/R)injury has been widely reported.Dental pulp-derived mesenchymal stem cells(DP-MSCs)have therapeutic effects on variou...Background:The protective effect of mesenchymal stem cells(MSCs)on cardiac ischemia-reperfusion(I/R)injury has been widely reported.Dental pulp-derived mesenchymal stem cells(DP-MSCs)have therapeutic effects on various diseases,including diabetes and cirrhosis.This study aimed to determine the therapeutic effects of DP-MSCs on I/R injury and elucidate the underlying mechanism.Methods:Myocardial I/R injury model mice were treated with DP-MSCs or a miR-19a-3p mimic.The infarct volume,fibrotic area,pyroptosis,inflammation level,and cardiac function were measured.Cardiomyocytes exposed to hypoxia-reoxygenation were transfected with the miR-19a-3p mimic,miR-19a-3p inhibitor,or negative control.Pyroptosis and protein expression in the interferon regulatory factor 8/mitogen-activated protein kinase(IRF-8/MAPK)pathway were measured.Results:DP-MSCs protected cardiac function in cardiac I/R-injured mice and inhibited cardiomyocyte pyroptosis.The upregulation of miR-19a-3p protected cardiac function,inhibited cardiomyocyte pyroptosis,and inhibited IRF-8/MAPK signaling in cardiac I/R-injured mice.DP-MSCs inhibited cardiomyocyte pyroptosis and the IRF-8/MAPK signaling by upregulating the miR-19a-3p levels in cardiomyocytes injured by I/R.Conclusion:DP-MSCs protected cardiac function by inhibiting cardiomyocyte pyroptosis through miR-19a-3p under I/R conditions.展开更多
Cellular senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic d...Cellular senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic differentiation and the senescence of MSCs,but its exact function and mechanism remain unclear.We found IGFBP7 promoted the osteogenic differentiation and prevented the senescence of dental pulp-derived MSCs(DPSCs),as observed in the gain-of-function and lossof-function analyses,the senescence-associated marker p21 showed the most pronounced expression changes.We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism,resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter,thereby reducing the transcription of p21,which ultimately prevents DPSCs senescence and promotes tissue regeneration.The activation of the mitochondrial electron transport chain(ETC)by Coenzyme Q10 could rescue the promotion of DPSC senescence induced by the knockdown of IGFBP7,whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC senescence induced by IGFBP7 overexpression.In conclusion,our present results reveal a novel function of IGFBP7 in preventing DPSC senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription,suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.展开更多
基金supported by grants from the National High Level Hospital Clinical Research Funding(No.BJ-2022-117)the special project on basic and applied research of clinical medicine of Shanghai Wu Mengchao Medical Science and Technology Foundation(No.JJHXM-2019018)+1 种基金Beijing Hospital Research Project(No.BJ-2019-147)Beijing Jiekai Cardiovascular Health Foundation(No.2022-062).
文摘Background:The protective effect of mesenchymal stem cells(MSCs)on cardiac ischemia-reperfusion(I/R)injury has been widely reported.Dental pulp-derived mesenchymal stem cells(DP-MSCs)have therapeutic effects on various diseases,including diabetes and cirrhosis.This study aimed to determine the therapeutic effects of DP-MSCs on I/R injury and elucidate the underlying mechanism.Methods:Myocardial I/R injury model mice were treated with DP-MSCs or a miR-19a-3p mimic.The infarct volume,fibrotic area,pyroptosis,inflammation level,and cardiac function were measured.Cardiomyocytes exposed to hypoxia-reoxygenation were transfected with the miR-19a-3p mimic,miR-19a-3p inhibitor,or negative control.Pyroptosis and protein expression in the interferon regulatory factor 8/mitogen-activated protein kinase(IRF-8/MAPK)pathway were measured.Results:DP-MSCs protected cardiac function in cardiac I/R-injured mice and inhibited cardiomyocyte pyroptosis.The upregulation of miR-19a-3p protected cardiac function,inhibited cardiomyocyte pyroptosis,and inhibited IRF-8/MAPK signaling in cardiac I/R-injured mice.DP-MSCs inhibited cardiomyocyte pyroptosis and the IRF-8/MAPK signaling by upregulating the miR-19a-3p levels in cardiomyocytes injured by I/R.Conclusion:DP-MSCs protected cardiac function by inhibiting cardiomyocyte pyroptosis through miR-19a-3p under I/R conditions.
基金the National Natural Science Foundation of China(82030031,81991504,92149301,82001067)the Chinese Research Unit of Tooth Development and Regeneration,Academy of Medical Sciences(2019-12M-5-031)+7 种基金the Beijing Municipal Science and Technology Commission(Z181100001718208)the Beijing Municipal Education Commission(119207020201)Beijing Advanced Innovation Center for Big Data-based Precision Medicine(PXM2021_014226_000026)the Beijing Municipal Government(Beijing Scholar program PXM2020_014226_000005,PXM2021_014226_000020)Innovation Research Team Project of Beijing Stomatological Hospital,Capital Medical University(CXTD202201)Beijing Municipal Administration of Hospitals’Youth Program(QML20191504)Scientific Research Common Program of Beijing Municipal Commission of Education(KM202110025009)Beijing Talents Fund(2018000021469G285)。
文摘Cellular senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic differentiation and the senescence of MSCs,but its exact function and mechanism remain unclear.We found IGFBP7 promoted the osteogenic differentiation and prevented the senescence of dental pulp-derived MSCs(DPSCs),as observed in the gain-of-function and lossof-function analyses,the senescence-associated marker p21 showed the most pronounced expression changes.We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism,resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter,thereby reducing the transcription of p21,which ultimately prevents DPSCs senescence and promotes tissue regeneration.The activation of the mitochondrial electron transport chain(ETC)by Coenzyme Q10 could rescue the promotion of DPSC senescence induced by the knockdown of IGFBP7,whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC senescence induced by IGFBP7 overexpression.In conclusion,our present results reveal a novel function of IGFBP7 in preventing DPSC senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription,suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.
