H/ACA Box Small Nucleolar RNA 7A Promotes the Self-Renewal of Human Umbilical Cord Mesenchymal Stem Cells

Abstract

Human umbilical cord blood derived mesenchymal stem cells (uMSC) are pluripotent cells that have been now considered as a promising candidate for various cell-based therapies. However, their limited in vitro proliferation ability and the gradual loss of pluripotency set barricades for further usages. Emerging evidence suggests that small nucleolar RNAs (snoRNA) are actively involved in cell proliferation especially in tumor cells, but their roles in stem cells are largely unknown. In this study, we demonstrated that H/ACA box small nucleolar RNA 7A (SNORA7A) is inversely correlated to the decreased proliferation rate during in vitro passaging of uMSC. Further investigations indicate that SNORA7A overexpression can promote uMSC proliferation and self-renewal. The inhibition of SNORA7A using antisense oligonucleotides significantly reduces the expression and the binding of SNORA7A to DKC1, core protein that essential to form small nucleolar ribonucleo-particles (snoRNP) complex and catalyze pseudouridines in 28S RNA. And the inhibition also significantly suppresses uMSC proliferation and self-renewal. Moreover, overexpression of SNORA7A transcripts with mutations of binding regions for snoRNP core proteins and 28S RNA did not induce proliferation and self-renewal. Besides, SNORA7A also suppresses both the osteogenic and adipogenic differentiation, strengthening its self-renewal maintaining roles in uMSC. Taken together, our study for the first time showed that H/ACA box snoRNAs are actively involved in MSC proliferation as well as pluripotency control, and we identify SNORA7A as one of the critical snoRNAs that regulate the proliferation and self-renewal of uMSC through snoRNP recruiting. STEM CELLS 2017;35:222-235 SIGNIFICANCE STATEMENTThe endogenous H/ACA box small nucleolar RNA 7A is critical for the proliferation of human umbilical cord mesemchymal stem cells through recuiting small nucleolar ribonucleo-particles. This finding may increase our understanding for the regulation network of stem cell biology, and may have the further implications in stem cells clinical applications.

H/ACA box small nucleolar RNA 7B acts as an oncogene and a potential prognostic biomarker in breast cancer

“…Among these paralogues, SNORA7B and SNORA7A are over 98% identical and target the same 28S rRNA pseudouridylation sites [30, 31]. Zhang et al [32] demonstrated that both SNORA7B and SNORA7A could promote the self-renewal of human umbilical cord blood-derived mesenchymal stem cells (uMSCs). The SNORA7B gene is located on chromosome 3q21 as an intron in the RPL32P3 gene.…”

Neuronal differentiation induces SNORD115 expression and is accompanied by post-transcriptional changes of serotonin receptor 2c mRNA

“…The exact role of PWS locus orphan snoRNAs remains to be determined. New and unexpected roles have been ascribed to several canonical and orphan snoRNAs in recent years ( 27 , 48 – 52 and reviewed in 53 ), straitening our convictions that this class of non-coding RNAs is more than a simple regulator of rRNA decoration.…”

Regulation of protein-coding gene and long noncoding RNA pairs in liver of conventional and germ-free mice following oral PBDE exposure

“…Conversely, the top most down-regulated genes by BDE-47 included glutamic-oxaloacetic transaminase 1 (Got1), which is important for amino acid metabolism and the urea and tricarboxylic acid cycles [ 122 ]; Sestrin 2 (Sesn2) and dopachrome tautomerase (Dct), both of which protect cells from oxidative stress [ 123 , 124 ]; ephrin type-A receptor A2 (Epha2), which mediates neural development [ 125 ]; and small nucleolar RNA 7A (Snora7a). Snora7a has been reported to promote cell proliferation and suppress differentiation in mesenchymal stem cell [ 126 ]. These results suggested that without the presence of gut microbiome, not only steroid and bile acid signaling pathways, but the cellular signaling were distinctly regulated by BDE-47 in GF mice.…”