MicroRNA let‐7c‐5p promotes osteogenic differentiation of dental pulp stem cells by inhibiting lipopolysaccharide‐induced inflammation via HMGA2/PI3K/Akt signal blockade

Abstract

Summary Pulpitis suppressed the level of let‐7c‐5p that promotes osteogenesis and bone formation by repressing HMGA2. In the current study, the function of let‐7c‐5p in the inflammation and osteogenesis in dental pulp stem cells (DPSCs) was explored. The level of let‐7c‐5p in DPSCs was up‐regulated, and the cells were subjected to lipopolysaccharide (LPS) to induce inflammation. The effect of let‐7c‐5p on cell proliferation potential, osteogenic differentiation potential, and activity of HMGA2/PI3K/Akt pathway was detected. The administration of LPS suppressed the cell proliferation of DPSCs and suppressed calcium deposition, activity of alkaline phosphatase (ALP), and levels of OCN, OPN, OSX, MSX2, and RUNX2 in inflamed DPSCs. The impaired osteogenic differentiation of inflamed DPSCs was associated with the increased levels of HMGA2, p‐PI3K, and p‐Akt. In let‐7c‐5p‐overexpressed inflamed DPSCs, the proliferation and osteogenic differentiation potential of DPSCs were restored, and the activation of HMGA2/PI3K/Akt signalling was inhibited. In rat pulpitis models, the injection of let‐7c‐5p agomir restored the osteogenic differentiation potential of dental pulp cells and inhibited HMGA2/PI3K/Akt signalling. The findings demonstrated the anti‐inflammation and pro‐osteogenesis effect of let‐7c‐5p during the attack of pulpitis, which depended on the inhibition of HMGA2/PI3K/Akt signalling.

MiR-26a inhibits the inflammatory response of microglia by targeting HMGA2 in intracerebral hemorrhage

“…HMGA2, a member of the HMGA family, has an AT-hook DNA-binding motif and plays an important role in tumorigenesis, cell proliferation, cell transformation, and inflammation. 27 A previous study verified that elevation of HMGA2 notably promoted the release of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), while downregulation of HMGA2 remarkably attenuated the release of proinflammatory cytokines, suggesting that HMGA2 positively regulates inflammation. 28 In this study, we found that overexpression of miR-26a remarkably inhibited the release of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) in LPS-treated microglial cells.…”

Epigenetic Regulation of Dental Pulp Stem Cell Fate

“…These inflammatory responses are reversed in the presence of let-7c-5p overexpression in LPS-induced DPSCs. It has been reported that let-7c-5p protects DPSCs from inflammation by directly repressing DMP1 and promotes the osteogenic differentiation through inhibition of HMGA2/PI3K/Akt signaling [ 167 , 168 ]. Besides, DPSCs treated with TNF- α exhibit increased expression of Fyn, a member of the protein tyrosine kinase Src family, which is related to inflammation and odontogenesis; however, the expression of miR-125a-3p is decreased.…”

Conserved and Divergent Modulation of Calcification in Atherosclerosis and Aortic Valve Disease by Tissue Extracellular Vesicles

“…(37) Therefore, valvular EV miR-125b-5p may modulate the expansion and differentiation of VICs down a pathogenic fibrocalcific lineage. The other miRs upregulated in valvular EVs are reported to exert control over osteochondrogenesis: let-7c-5p promotes osteogenic differentiation and bone formation by mesenchymal stem cells (MSCs) in response to inflammation through interactions with the HMGA2/PI3K/Akt signaling cascade,(38) while miR-574-3p is a mechanoresponsive miR (particularly relevant to the biomechanically-complex valvular microenvironment) known to regulate MSC chondrogenesis downstream of Sox9 via targeting of the retinoid X receptor (RXR)α. (39) Pathway analysis on the predicted targets of these miRs strongly implicated RUNX2, toll-like receptors, and mechanotransduction as key downstream pathological effectors of vascular EVs, while valvular EV miRs were linked to IL-17 and sphingolipid signaling pathways that are involved in valvular inflammatory cell infiltration and osteogenesis/calcification.…”