MiR-21/STAT3 Signal Is Involved in Odontoblast Differentiation of Human Dental Pulp Stem Cells Mediated by TNF-α

Abstract

Dental pulp stem cells (DPSCs), as one type of mesenchymal stem cells (MSCs), have the capability of self-renewal and multipotency to differentiate into several cell lineages, including osteogenesis, odontoblasts, chondrogenesis, neurogenesis, and adipogenesis. It has found that tumor necrosis factor-α (TNF-α) can promote osteogenic differentiation of human DPSCs in our previous studies. Other experimentation revealed that signal transducer and activator of transcription 3 (STAT3) underwent a rapid activation both in osteogenesis and inflammation microenvironment of MSCs in vitro. MicroRNAs (miRNAs or miRs) have been proved in previous studies to regulate MSCs differentiation in vitro. In this study, we identified miR-21 as a key miRNA contributed the functional axis of odontoblast differentiation induced by STAT3. It is observed that the expression of miR-21 and STAT3 increased gradually in low concentration (1-10 ng/mL) of TNF-α, while they were suppressed in high concentration (50-100 ng/mL). The upregulation of miR-21 may facilitate the odontoblast differentiation of DPSCs coordinating with STAT3. SiSTAT3 or treated by the inhibitor of STAT3, cucurbitacin I (Cuc I), significantly increased primary miR-21 expression along with decreased mature miR-21 expression. Meanwhile, the inhibition of miR-21 (anti-miR-21) decreased the activation of STAT3 as well as suppressed the marker proteins of odontoblast differentiation. The results revealed a new function of miR-21, suggesting that miR-21/STAT3 signal may act as a modulator within a complex network of factors to regulate odontoblast differentiation of human DPSCs. It may provide a novel therapeutic strategy to regulate the odontoblast differentiation of DPSCs.

Epigenetic Regulation of Dental Pulp Stem Cell Fate

“…Consistent with the above results, increased expression of miR-21, as well as signal transducer and activator of transcription 3 (STAT3), is observed at low concentrations of TNF- α , while the opposite results are observed at high concentrations. It is noteworthy that miR-21 and STAT3 form a positive feedback loop to regulate odontogenic differentiation [ 172 ]. These results reveal that miRNAs are associated with the inflammatory response of DPSCs and also provide a new perspective for the treatment of pulpitis.…”

miR-21-5p Under-Expression in Patients with Obstructive Sleep Apnea Modulates Intermittent Hypoxia with Re-Oxygenation-Induced-Cell Apoptosis and Cytotoxicity by Targeting Pro-Inflammatory TNF-α-TLR4 Signaling

“…Certain miRNAs, including miR-21 and miR-23a, are induced by TLR signaling or negatively regulate TLR signaling [14]. Specifically, miR-21 is involved in anti-inflammatory response via inhibiting TLR, NF-κB, IL-6, and TNF-α signaling pathway, while high concentrations of TNF-α inhibit miR-21 functional axis [15][16][17][18][19][20]. In contrast, miR-23a may be involved in pro-inflammatory response via enhancing TNF-α and IL-6 secretions, while TLR signaling can inhibit miR-23a expression [21][22][23].…”

Genome-wide identification of long noncoding RNAs and their competing endogenous RNA networks involved in the odontogenic differentiation of human dental pulp stem cells

“…In the research on ncRNAs and their roles in the odontogenic differentiation of hDPSCs, the most studied are miRNAs. miR-223-3p and miR-21 have been shown to promote odontogenic differentiation, while miR-143-5p, miR-140-5p, and miR-488 inhibit this process [41][42][43][44][45][46]. In 2016, Chen et al found that lncRNA differentiation antagonizing non-protein coding RNA (DANCR) inhibited the odontogenic differentiation of human dental pulp cells by inactivating the Wnt/β-catenin signaling pathway [16].…”