Abstract
BackgroundSeveral long non-coding RNAs (lncRNAs) have been associated with cell senescence, termed senescence-associated lncRNAs (SAL-RNAs). However, the mechanisms involved for SAL-RNAs in aging are not fully elucidated. In the present study, we investigated the effects of SAL-RNAs on aged human bone marrow-derived mesenchymal stem cells (hBM-MSCs), and the possible means to counteract such effects to improve the regenerative capacity of aged hBM-MSCs.MethodsBy comparing the lncRNAs expression of hBM-MSCs derived from young and old individuals, lnc-CYP7A1-1 was identified as being significantly increased with age. Using predictive software, the expression of Spectrin Repeat Containing Nuclear Envelope Protein 1 (SYNE1), was found to be decreased with age. Next, through lentiviral constructs, we downregulated the expression of lnc-CYP7A1-1 or SYNE1 in hBM-MSCs separately. Additionally, hBM-MSCs proliferation, survival, migration, and senescence were investigated in vitro. In vivo, lnc-CYP7A1-1 downregulated aged hBM-MSCs were implanted into infarcted mouse hearts after myocardial infarction (MI), and cardiac function was measured. Through lentivirus-mediated downregulation of lnc-CYP7A1-1 in aged hBM-MSCs, we revealed that cell senescence was decreased, whereas cell proliferation, migration, and survival were increased. On the other hand, downregulation of SYNE1, the target gene of lnc-CYP7A1-1, in young hBM-MSCs increased cell senescence, yet decreased cell proliferation, migration, and survival. Downregulation of lnc-CYP7A1-1 in aged hBM-MSCs induced cell rejuvenation, yet this effect was attenuated by repression of SYNE1. In vivo, transplantation of lnc-CYP7A1-1 downregulated old hBM-MSCs improved cardiac function after MI.ConclusionDown-regulation of lnc-CYP7A1-1 rejuvenated aged hBM-MSCs and improved cardiac function when implanted into the infarcted mouse hearts, possibly through its target gene SYNE1.
Highlights
Human bone marrow-derived mesenchymal stem cells (MSCs), with their abilities of multipotent potential and promoting regenerative processes in host tissues via paracrine signaling, show great promise in tissue repairing
Down-regulation of lnc-CYP7A1-1 rejuvenated aged Human bone marrow (hBM)-MSCs and improved cardiac function when implanted into the infarcted mouse hearts, possibly through its target gene SYNE1
Cell migration was detected by transwell and wound-scratch assays (Figures 1E–H), which both showed significantly lower migration rates (Figures 1F,H) in O compared to YhBM-MSCs
Summary
Human bone marrow (hBM)-derived mesenchymal stem cells (MSCs), with their abilities of multipotent potential and promoting regenerative processes in host tissues via paracrine signaling, show great promise in tissue repairing. This decreased potency of hBM-MSCs has a significant impact on the use of autologous stem cells for treating a predominantly older cohort of patients with cardiovascular disease (Li S.-H. et al, 2013; Li et al, 2018, 2019) Part of this reduced efficacy is due to hBM-MSCs taking on a senescent phenotype and losing their proliferative capacity (Yan et al, 2017). Mechanisms for SAL-RNAs involved in aging range from transcriptional repressors/activators (Dimitrova et al, 2014; Montes et al, 2015), mRNA stability (Kumar et al, 2014), protein localization (Wu et al, 2015)/ubiquitination (Yoon et al, 2013)/translation (Abdelmohsen et al, 2014), to telomere remodeling (Cusanelli and Chartrand, 2015) For their non-coding nature and particularities, lncRNAs are emerging as potential targets for anti-aging therapies (Tan and Bird, 2016). We investigated the effects of SAL-RNAs on aged human bone marrow-derived mesenchymal stem cells (hBM-MSCs), and the possible means to counteract such effects to improve the regenerative capacity of aged hBM-MSCs
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