Down-Regulation of Lnc-CYP7A1-1 Rejuvenates Aged Human Mesenchymal Stem Cells to Improve Their Efficacy for Heart Repair Through SYNE1

Abstract

Background: Several 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. Methods: By 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. Conclusion: Down-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.

Downregulation of ALKBH5 rejuvenates aged human mesenchymal stem cells and enhances their therapeutic efficacy in myocardial infarction

“…MSC‐based therapy has been identified as a promising intervention for MI because of the unique properties of MSCs: easy isolation and expansion, multiple lineage potential, and lack of immunogenicity. Nonetheless, their beneficial effects are dramatically hampered by their cellular senescence 29–31 . Compared with YMSCs, AMSCs display decreased proliferative capacity and reduced paracrine effects, especially their angiogenic capacity which is the major mechanism underlying MSC‐based therapy for MI 28,32 .…”

“…Nonetheless, their beneficial effects are dramatically hampered by their cellular senescence. [29][30][31] Compared with YMSCs, AMSCs display decreased proliferative capacity and reduced paracrine effects, especially their angiogenic capacity which is the major mechanism underlying MSC-based therapy for MI. 28,32 More importantly, AMSCs exhibit a decreased survival capacity in ischemic heart tissue.…”

Tumorigenic Aspects of MSC Senescence—Implication in Cancer Development and Therapy

“…Moreover, Dong et al discovered that long non-coding RNA (lnc), lnc-CYP7A1-1, stimulated senescence in human BM-MSCs, and its downregulation subsequently improved regenerative capacities and decreased cell senescence in vitro [116]. Consequently, transplantation of old human BM-MSCs with downregulated lnc-CYP7A1-1 improved cardiac function in mice after myocardial infarction.…”

LncRNA‐AK137033 inhibits the osteogenic potential of adipose‐derived stem cells in diabetic osteoporosis by regulating Wnt signaling pathway via DNA methylation

“… 19 , 20 With the gradual deepening of the research on LncRNAs, many studies have reported that LncRNAs regulate gene expression at the epigenetic, transcriptional, and post‐transcriptional levels, and have a potential regulatory effect on the cell fate of mesenchymal stem cells and the occurrence and development of specific diseases. 19 , 21 , 22 In particular, studies have confirmed that LncRNAs affect the expression of specific genes by regulating the DNA methylation level in their promoter region. 23 , 24 , 25 However, the molecular mechanism of LncRNAs in regulating the osteogenic differentiation and bone regeneration of DOP‐ASCs is unclear.…”