lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling

Abstract

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can undergo self-renewal and differentiate into multiple lineages. Osteogenic differentiation from MSCs is a well-orchestrated process and regulated by multiple signaling pathways. We previously demonstrated that BMP9 is one of the most potent osteogenic factors. However, molecular mechanism through which BMP9 governs osteoblastic differentiation remains to be fully understood. Increasing evidence indicates noncoding RNAs (ncRNAs) may play important regulatory roles in many physiological and/or pathologic processes. In this study, we investigate the role of lncRNA H19 in BMP9-regulated osteogenic differentiation of MSCs. We demonstrated that H19 was sharply upregulated at the early stage of BMP9 stimulation of MSCs, followed by a rapid decease and gradual return to basal level. This process was correlated with BMP9-induced expression of osteogenic markers. Interestingly, either constitutive H19 expression or silencing H19 expression in MSCs significantly impaired BMP9-induced osteogenic differentiation in vitro and in vivo, which was effectively rescued by the activation of Notch signaling. Either constitutive H19 expression or silencing H19 expression led to the increased expression of a group of miRNAs that are predicted to target Notch ligands and receptors. Thus, these results indicate that lncRNA H19 functions as an important mediator of BMP9 signaling by modulating Notch signaling-targeting miRNAs. Our findings suggest that the well-coordinated biphasic expression of lncRNA H19 may be essential in BMP9-induced osteogenic differentiation of MSCs, and that dysregulated H19 expression may impair normal osteogenesis, leading to pathogenic processes, such as bone tumor development.

The Long Intergenic Noncoding RNA 00707 Promotes Lung Adenocarcinoma Cell Proliferation and Migration by Regulating Cdc42

“…Although lncRNAs were previously regarded as “transcriptional noise”, they are now considered as key regulators of physiological processes and disorders including cancer [11, 13]. For instance, lncRNA H19 functions as an essential mediator of bone morphogenetic protein 9-induced osteogenesis differentiation of mesenchymal stem cells through Notch signaling, and dysregulation of H19 expression may impair normal osteogenesis [14]. Magistri et al showed using next generation RNA sequencing that several lncRNAs are differentially expressed in late-onset Alzheimer’s disease brain tissues [15].…”

Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

“…49 Liver weights of the mice lacking H19 expression markedly increased immediately after birth with significant increases in cell proliferation, F I G U R E 7 H19 promotes lipid accumulation by up-regulating mTORC1 and MLXIPL signalling pathways in hepatocyte transplantation assay. 21 It was also reported that H19 inhibited adipocyte differentiation of bone marrow MSCs through epigenetic modulation of HDACs, 51 while a recent study suggests that H19 may regulate the balance between osteogenic and adipogenic differentiation, and enhance adipogenic differentiation through sponging miR-188 and miR-30a, respectively. A, Paraffin sections of the retrieved cell masses were subjected to H & E staining.…”

“…21 Recombinant adenovirus Ad-H19 was produced and/or amplified in 293pTP or RAPA cells. 21,29 The resulting recombinant adenoviral vectors were used to generate adenovirus Ad-siH19 or Ad-siMlxipl, each of which contains the pooled three siRNAs, and also co-expresses the RFP marker gene. For constructing the adenoviral vectors expressing siRNAs targeting mouse H19 and mouse Mlxipl/ChREBP, we employed our recently developed pSOS system, in which siRNA expression is driven by the converging U6-H1 promoters.…”

“…21 The primary hepatocytes were treated with adenovi- 21 The primary hepatocytes were treated with adenovi- …”

“…16,17 H19 is located in a highly conserved imprinted gene cluster containing a neighbouring reciprocally imprinted gene for Igf2. 21 Nonetheless, the diverse biological functions of H19 remain to be fully understood. H19 expression is strongly induced during embryogenesis and down-regulated after birth, except in adult skeletal muscle and heart.…”