LncRNA LYPLAL1-AS1 rejuvenates human adipose-derived mesenchymal stem cell senescence via transcriptional MIRLET7B inactivation

Abstract

Background: Mesenchymal stem cell (MSC) senescence is a phenotype of aging. Long noncoding RNAs (lncRNAs) are emerging as potential key regulators of senescence. However, the role of lncRNAs in MSC senescence remains largely unknown. Results: We performed transcriptome analysis in senescent human adipose-derived MSCs (hADSCs) and identified that the lncRNA LYPLAL1 antisense RNA1 (LYPLAL1-AS1) was significantly downregulated in senescent hADSCs. LYPLAL1-AS1 expression in peripheral blood was lower in middle-aged healthy donors than in young adult donors, and correlated negatively with age. Knockdown of LYPLAL1-AS1 accelerated hADSC senescence, while LYPLAL1-AS1 overexpression attenuated it. Chromatin isolation by RNA purification (ChIRP) sequencing indicated that LYPLAL1-AS1 bound to the MIRLET7B promoter region and suppressed its transcription activity, as demonstrated by dual-luciferase assay. miR-let-7b, the transcript of MIRLET7B, was upregulated during hADSC senescence and was regulated by LYPLAL1-AS1. Furthermore, miR-let-7b mimics promoted hADSC senescence, while the inhibitors repressed it. Finally, LYPLAL1-AS1 overexpression reversed miR-let-7b-induced hADSC senescence. Conclusions: Our data demonstrate that LYPLAL1-AS1 rejuvenates hADSCs through the transcriptional inhibition of MIRLET7B. Our work provides new insights into the mechanism of MSC senescence and indicates lncRNA LYPLAL1-AS1 and miR-let-7b as potential therapeutic targets in aging.