Long noncoding RNA C21orf121/bone morphogenetic protein 2/microRNA‐140‐5p gene network promotes directed differentiation of stem cells from human exfoliated deciduous teeth to neuronal cells

Abstract

Previous studies have revealed that long noncoding RNA (lncRNA) and microRNA play a crucial role in autism, which is a childhood neurodevelopmental disorder with complicated genetic origins. Hence, the study concerns whether lncRNA C21orf121/bone morphogenetic proteins 2 (BMP2)/miR‐140‐5p gene network affects directed differentiation of stem cells from human exfoliated deciduous teeth (SHED) to neuronal cells in rats with autism. Autism models were successfully established. The neuron cells that differentiated from SHED cell were identified. The expression of lncRNA C21orf121, miR‐140‐5p, BMP2, Nestin, βIII‐tubulin, and microtubule‐associated protein 2 (MAP2) and the expression of neuron‐specific enolase (NSE) were examined. Besides, the gap junction (GJ) function of SHED, the intracellular free Ca 2+ concentration, and the social behavior and repetitive stereotyped movements of rats in autism were detected. The target relationship between lncRNA C21orf121 and miR‐140‐5p and that between miR‐140‐5p and BMP2 were also verified. Firstly, we successfully isolated SHED and identified the differentiated neurons of SHED. Besides, the expression of BMP2, MAP2, Nestin, βIII‐tubulin, NSE positive rate, GJ function, and intracellular free Ca 2+ concentration were increased with the upregulation of C21orf121 and downregulation of miR‐140‐5p, and accumulated time of repetitive stereotyped movements decreased and the frequency of social behavior increased. The results indicate that lncRNA C21orf121 as a competing endogenous RNA competes with BMP2 binding to miR‐140‐5p, thereby promoting SHED to differentiate into neuronal cells via upregulating BMP2 expression.

Differential lncRNA/mRNA Expression Profiling and Functional Network Analyses in Bmp2 Deletion of Mouse Dental Papilla Cells

“…Several canonical and non-canonical Bmp2 signaling pathways have been reported involved in odontogenesis ( Cho et al, 2010 ; Qin et al, 2012a ; Qin et al, 2012b ; Washio et al, 2012 ; Qin et al, 2014 ). Recently accumulated evidence has demonstrated that lncRNAs play biological roles in dental cell proliferation, cell proliferation, and tooth development through the regulation of growth and transcriptional factors ( Zheng and Jia, 2016 ; Liu et al, 2018 ; Gil and Ulitsky, 2020 ; Wang et al, 2020 ; Li et al, 2021 ; Mirzadeh Azad et al, 2021 ). The cross talk between the Bmp2 signaling pathway and lncRNAs in dental cell proliferation, cell differentiation, and odontogenesis remains largely unclear.…”

“…It suggested that Bmp2 regulates dental differentiation and dentinogenesis via these genes. It has been documented that the interplay of Bmp2 signal–associated mRNAs and lncRNAs regulates tooth development and formation ( Liu et al, 2018 ; Zhong et al, 2020 ). This study showed that several novel lncRNAs such as lncRNA87211.1, lncRNA87189.1, and lncRNA86888.1 co-expressed with those mRNAs ( Figure 6 ).…”

“…Accumulating evidence indicated that Bmp2 is capable of regulating a lot of bone/dentin-related gene expressions and transcriptional factors as well as dental cell proliferation and differentiation in tooth development ( Chen et al, 2008 ; Cho et al, 2010 ; Oh et al, 2012 ; Yang et al, 2017 ). Additionally, cross talk has been described between Bmp signaling–associated mRNAs and non-coding RNAs during dental cell proliferation and differentiation ( Wang F. et al, 2017 ; Wang J. et al, 2017 ; Liu et al, 2018 ; Liao et al, 2020 ; He et al, 2021 ).…”

The functions of long non-coding RNAs in neural stem cell proliferation and differentiation

“…LncRNA MSNP1AS expression was elevated in the postmortem cerebral cortex of individuals with ASD, which was mimicked by overexpression of MSNP1AS in human NPCs reduced neurite number and neurite length by disrupting moesin protein level, when knockdown of MSNP1AS blocked 318 genes expression, most of which participating in chromatin organization and immune response [72,79]. Moreover, lncRNA C21orf121 overexpression promoted conversion of stem cells from human exfoliated deciduous teeth into neuronal cells via acting as ceRNA of miR-140-5p to regulate BMP2 expression, which may provide a new therapeutic tool for ASD [80] (Table 3). Furthermore, lncRNAs are involved in angiogenesis that NPCs in SVZ and SGZ migration to ischemic zone for restoration of blood supply after ischemic stroke [81].…”

Multidifferentiation potential of dental-derived stem cells

“…Yang et al[ 78 ] found that Noggin overexpression combined with the Rho kinase inhibitor Y-27632 exhibited a synergistic effect in promoting differentiation of SHED into neuron-like cells[ 78 ]. The lncRNA C21orf121 promotes SHED differentiation into neuronal cells by upregulating the expression of BMP2, acting as a competing endogenous RNA to compete with BMP2 binding to miR-140-5p[ 79 ]. SHED in polyglycolic acid tubes combined with autografting can regenerate the mandibular branch of the rat facial nerve[ 80 ].…”