title: SRT1720 promotes survival of aged human mesenchymal stem cells via FAIM: a pharmacological strategy to improve stem cell-based therapy for rat myocardial infarction.
abstract: SIRT1 has been proved to rejuvenate and improve the therapeutic efficacy of aged rat mesenchymal stem cells (MSCs). Herein, we investigate the protective effect of pretreatment with SIRT1 activator SRT1720 on aged human MSCs (hMSCs). The optimized pretreatment condition for aged hMSCs was determined to be 0.5 μM SRT1720 for 24 h by monitoring the survival of aged hMSCs subjected to serum deprivation±hypoxia and±500 μM hydrogen peroxide (H2O2). Pretreatment with these conditions increased the survival of aged hMSCs 1 day (2.7-fold) and 3 days (1.9-fold) after being transplanted into a rat myocardial infarction (MI) model created by ligation of the left anterior descending (LAD) coronary artery. Transplantation with SRT1720 pretreated aged hMSCs achieved increased left ventricular ejection fraction (58.9±3.6 versus 52.8±5%) and angiogenesis with reduced fibrosis of rat hearts as compared to DMSO pretreated group 28 days following MI. Unbiased transcriptome analysis conducted on aged hMSCs under oxidative stress indicated the Fas apoptosis inhibitory molecule (FAIM) was significantly upregulated following SRT1720 pretreatment (14.9±0.2-folds). Moreover, the anti-apoptotic effect of SRT1720 was mitigated by FAIM knockdown with a small interfering RNA-targeted FAIM. These results indicated that pretreatment with SRT1720 improves survival of aged hMSCs, and enhances their therapeutic efficacy for rat myocardial infarction (MI). Upregulation of FAIM possibly involves in the mechanisms of the protective effects.
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Xianbao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.|Department of Cardiology, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, China.
authors.forename: Dexing
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Zhiru
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Wang
authors.affiliation: Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Lengmei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, Zhejiang, China.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D002470:Cell Survival; D016922:Cellular Senescence / Q000187:drug effects*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C421307:FAIM protein, human; C586050:FAIM protein, rat; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; C447939:SIRT1 protein, human; C488368:Sirt1 protein, rat; D056564:Sirtuin 1