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      SRT1720 promotes survival of aged human mesenchymal stem cells via FAIM: a pharmacological strategy to improve stem cell-based therapy for rat myocardial infarction

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          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 (H 2O 2). 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.

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          Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

          Jill Milne, Philip Lambert, Simon Schenk … (2007)
          Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
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            Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts.

            Shuanhu Zhou, Joel Greenberger, Michael Epperly … (2008)
            In vivo and in vitro studies indicate that a subpopulation of human marrow-derived stromal cells (MSCs, also known as mesenchymal stem cells) has potential to differentiate into multiple cell types, including osteoblasts. In this study, we tested the hypothesis that there are intrinsic effects of age in human MSCs (17-90 years). We tested the effect of age on senescence-associated beta-galactosidase, proliferation, apoptosis, p53 pathway genes, and osteoblast differentiation in confluent monolayers by alkaline phosphatase activity and osteoblast gene expression analysis. There were fourfold more human bone MSCs (hMSCs) positive for senescence-associated beta-galactosidase in samples from older than younger subjects (P < 0.001; n = 17). Doubling time of hMSCs was 1.7-fold longer in cells from the older than the younger subjects, and was positively correlated with age (P = 0.002; n = 19). Novel age-related changes were identified. With age, more cells were apoptotic (P = 0.016; n = 10). Further, there were age-related increases in expression of p53 and its pathway genes, p21 and BAX. Consistent with other experiments, there was a significant age-related decrease in generation of osteoblasts both in the STRO-1+ cells (P = 0.047; n = 8) and in adherent MSCs (P < 0.001; n = 10). In sum, there is an age-dependent decrease in proliferation and osteoblast differentiation, and an increase in senescence-associated beta-galactosidase-positive cells and apoptosis in hMSCs. Up-regulation of the p53 pathway with age may have a critical role in mediating the reduction in both proliferation and osteoblastogenesis of hMSCs. These findings support the view that there are intrinsic alterations in human MSCs with aging that may contribute to the process of skeletal aging in humans.
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              SIRT1 in neurodevelopment and brain senescence.

              A Herskovits, Leonard Guarente (2014)
              Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases that have traditionally been linked with calorie restriction and aging in mammals. These proteins also play an important role in maintaining neuronal health during aging. During neuronal development, the SIR2 ortholog SIRT1 is structurally important, promoting axonal elongation, neurite outgrowth, and dendritic branching. This sirtuin also plays a role in memory formation by modulating synaptic plasticity. Hypothalamic functions that affect feeding behavior, endocrine function, and circadian rhythmicity are all regulated by SIRT1. Finally, SIRT1 plays protective roles in several neurodegenerative diseases including Alzheimer's, Parkinson's, and motor neuron diseases, which may relate to its functions in metabolism, stress resistance, and genomic stability. Drugs that activate SIRT1 may offer a promising approach to treat these disorders. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Death Dis
                Journal ID (iso-abbrev): Cell Death Dis
                Title: Cell Death & Disease
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2041-4889
                Publication date (Print): April 2017
                Publication date (Electronic): 06 April 2017
                Publication date PMC-release: 1 April 2017
                Volume: 8
                Issue: 4
                Page: e2731
                Affiliations
                [1 ]Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, China
                [2 ]Provincial Key Laboratory of Cardiovascular Research , Hangzhou, Zhejiang, China
                [3 ]Department of Cardiology, Ningbo Medical Center Lihuili Eastern Hospital , Ningbo, China
                Author notes
                [* ]Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine , 88 Jiefang Road, Hangzhou, Zhejiang 310009, China. Tel:+86 571 8731 5001; Fax: +86 571 8703 7885; E-mail: jian_an_wang@ 123456yahoo.com
                [4]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: cddis2017107
                DOI: 10.1038/cddis.2017.107
                PMC ID: 5477573
                PubMed ID: 28383554
                SO-VID: c50c4758-22f1-4ffc-97bd-5fd133326c0e
                Copyright © Copyright © 2017 The Author(s)
                License:

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 04 October 2016
                Date revision received : 24 January 2017
                Date accepted : 03 February 2017
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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