Vacuolar protein sorting 4B regulates the proliferation and odontoblastic differentiation of human dental pulp stem cells through the Wnt-β-catenin signalling pathway

Abstract

Our previous studies have revealed that a dominant mutation in vacuolar protein sorting 4B (VPS4B), a member of the AAA ATPase family, causes dentin dysplasia type I. The purpose of the present study was to investigate the roles of VPS4B in human dental pulp stem cells (hDPSCs) and to elucidate the underlying molecular mechanisms. In this study, we found that VPS4B was highly expressed in the dental pulp cells of the mouse molar tooth germ, and the expression of VPS4B increased significantly during the odontoblastic differentiation of hDPSCs. VPS4B downregulation inhibited the proliferation, migration, and odontoblastic differentiation of hDPSCs. Moreover, treatment with lithium chloride, an agonist of the Wnt-b-catenin signalling pathway, partially reversed the VPS4B knockdown-driven suppression of proliferation and of odontoblastic differentiation of hDPSCs. Collectively, our findings indicate that VPS4B, via Wnt-b-catenin signalling, acts as a regulator of the proliferation and differentiation of hDPSCs. Our results suggest potential therapeutic avenues for dentin formation and regenerative endodontics in patients with dentin dysplasia type I. ARTICLE HISTORY

N-Cadherin Regulates the Odontogenic Differentiation of Dental Pulp Stem Cells via β-Catenin Activity

“…This could be further supported by previous research reporting that the expression of β-catenin was significantly upregulated during odontogenic differentiation of DPSCs, and knockdown of βcatenin disrupted odontogenic differentiation, which could be reversed by the lithium chloride-induced accumulation of βcatenin (Han et al, 2014). Besides, mounting evidence shows that numerous regulators, including but not limited to enhancer of zeste homolog 2, Stathmin, vacuolar protein sorting 4B, R-Spondin 2, and lncRNA DANCR, regulate the odontogenic differentiation of DPSCs through the Wnt/β-catenin pathway (Chen et al, 2016;Li et al, 2018;Pan et al, 2019;Zhang et al, 2019;Gong et al, 2020).…”

MicroRNA-488-3p Regulates Neuronal Cell Death in Cerebral Ischemic Stroke Through Vacuolar Protein Sorting 4B (VPS4B)

“…Previous studies have shown that VPS4 affects extracellular secretion and lysosomal and cell proliferation and differentiation through regulating specific signaling pathways. 32,33 Some scholars found that the level of VPS4B in the brain tissues was significantly increased after MCAO and the activity of caspase-3 protein was up-regulated to contribute for neuron apoptosis. 34 Our study further demonstrated that VPS4B was a direct target of miR-488-3p and verified that miR-488-3p could inhibit the expression of VPS4B in OGD/R-treated neurons.…”

“…of human dental pulp stem cells (hDPSCs). 32 In Parkinson's Disease, VPS4 acts as the target site of alphasynuclein (α-SYN) in regulation of lysosomal or extracellular secretion, leading to intercellular propagation of Lewy pathology. 33 It was found that VPS4B level was significantly increased in the hippocampus of adult mice with Middle Cerebral Artery Occlusion (MCAO).…”

VPS4B mutation impairs the osteogenic differentiation of dental follicle cells derived from a patient with dentin dysplasia type I

“…Until now, few studies have compared cell proliferation between patients with DD-I and healthy individuals. One study 39 performed proliferation assays using Cell Counting Kit-8, which indicated that human dental pulp stem cells (hDPSCs) transduced with an shRNA-Vps4b lentivirus proliferated slower than their counterparts transduced with a control lentivirus over 7 days. However, in our study, the DD-I DFCs growth rates were significantly increased compared to the control DFCs growth rates after 3 days of culture.…”

“… 41 – 43 One study showed that VPS4B acts as a regulator of hDPSC proliferation and differentiation via Wnt-β-catenin signaling. 39 Moreover, it has been demonstrated that the overexpression or knockdown of VPS4B in human gingival fibroblasts markedly increased or decreased the expression of CHMP4B, Wnt5a, and β-catenin. The VPS4B -CHMP4B-Wnt5a-β-catenin regulatory pathway might regulate odontoblast differentiation and root formation.…”