Recently, numerous types of human dental tissue‐derived mesenchymal stem cells (MSCs) have been isolated and characterized, including dental pulp stem cells, stem cells from exfoliated deciduous teeth, periodontal ligament stem cells, dental follicle progenitor cells, alveolar bone‐derived MSCs, stem cells from apical papilla, tooth germ progenitor cells, and gingival MSCs. All these MSC‐like cells exhibit self‐renewal, multilineage differentiation potential, and immunomodulatory properties. Several studies have demonstrated the potential advantages of dental stem cell‐based approaches for regenerative treatments and immunotherapies. This review outlines the properties of various dental MSC‐like populations and the progress toward their use in regenerative therapy. Several dental stem cell banks worldwide are also introduced, with a view toward future clinical application. Stem Cells 2015;33:627–638

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is responsible for approximately 15% of cancer-related mortality in children. Aberrant activation of cyclin-dependent kinases (CDKs) has been shown to contribute to tumor cell progression in many cancers including NB. Therefore, small molecule inhibitors of CDKs comprise a strategic option in cancer therapy. Here we show that a novel multiple-CDK inhibitor, dinaciclib (SCH727965, MK-7965), exhibits potent anti-proliferative effects on a panel of NB cell lines by blocking the activity of CDK2 and CDK9. Dinaciclib also significantly sensitized NB cell lines to the treatment of chemotherapeutic agents such as doxorubicin (Dox) and etoposide (VP-16). Furthermore, dinaciclib revealed in vivo antitumor efficacy in an orthotopic xenograft mouse model of two NB cell lines and blocked tumor development in the TH-MYCN transgenic NB mouse model. Taken together, this study suggests that CDK2 and CDK9 are potential therapeutic targets in NB and that abrogating CDK2 and CDK9 activity by small molecules like dinaciclib is a promising strategy and a treatment option for NB patients.

How Wnt signalling including canonical and non-canonical pathways are initiated at the cell surface is not completely understood. Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. Importantly, through direct binding to Frz, LRP5/6 are able to prevent Frz-regulated non-canonical pathway activation and further non-canonical pathway-mediated tumour metastasis. Knockdown of endogenous LRP5/6 promotes otherwise-nonaggressive tumour cells to migrate in vitro, whereas a soluble recombinant protein of LRP6 ectodomain suppresses migration and metastasis of otherwise-aggressive tumour cells in vitro and in vivo. Furthermore, the expression level of membrane LRP5/6 correlates inversely with metastasis in mouse and human breast cancer. Our study suggests a previously unrecognized mode of receptor interaction, revealing the mechanism of LRP5/6 in inhibition of non-canonical pathway, and a possible clinical use of the LRP6 ectodomain to impede metastasis.

Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) are types of human dental tissue‑derived mesenchymal stem cells (MSCs). These cells possess a capacity for self‑renewal, multilineage differentiation potential and immunomodulatory functions. Previous studies have reported that DPSCs and SHED may be beneficial in regenerative treatments and immunotherapy. The substantial expansion of cells in vitro is a prerequisite to obtaining adequate cell numbers required for cell‑based therapy. However, the regeneration and clinical potential of MSCs diminishes with long‑term cell culture amplification. To assess the alterations in SHED and DPSCs characteristics that underlie cellular senescence and result from extended in vitro amplification, the biological properties of SHED and DPSCs at passages 4 (P4) and 20 (P20) were compared. The cells underwent senescence following serial expansion to P20, as determined by altered cell morphology, decreased proliferation and migration capacity, attenuated differentiation potential, elevated senescence‑associated β‑galactosidase (SA‑β‑gal)‑positive rates and increased apoptosis. The phenotypic changes were also accompanied by a marked increase in the expression of p53, p21 and p16Ink4a. The present study also identified that senescent DPSCs exhibited an increased number of positive cells in SA‑β‑gal staining and demonstrated varying expressions of p53, p21 and p16Ink4a in comparison with SHED, indicating the involvement of diverse pathways in cellular senescence during long‑term sequential in vitro culture and passage. Furthermore, at early and late passages, SHED exhibited a higher proliferation rate and osteogenic differentiation capability when compared with DPSCs. In addition, both cell types maintained their characteristic immunophenotype during long‑term cultivation, while the expression levels of CD73 were higher in SHED at P20. The present study concluded that notable alterations were exhibited in SHED and DPSCs during the process of extensive expansion in vitro and the results may provide guidance for the selection of safe and effective expanded SHED and DPSCs for regenerative medicine and therapy.

Objective—: Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Interleukin 37 (IL-37) is a newly identified cytokine of the IL-1 family, some members of which are important in inflammation and angiogenesis. However, the function of IL-37 in angiogenesis remains unknown. We aimed to explore the regulatory role of IL-37 in pathological and physiological angiogenesis. Approach and Results—: We found that IL-37 was expressed and secreted in endothelial cells and upregulated under hypoxic conditions. IL-37 enhanced endothelial cell proliferation, capillary formation, migration, and vessel sprouting from aortic rings with potency comparable with that of vascular endothelial growth factor. IL-37 activates survival signals including extracellular signal-regulated kinase 1/2 and AKT in endothelial cells. IL-37 promoted vessel growth in implanted Matrigel plug in vivo in a dose-dependent manner with potency comparable with that of basic fibroblast growth factor. In the mouse model of retinal vascular development, neonatal mice administrated with IL-37 displayed increased neovascularization. We demonstrated further that IL-37 promoted pathological angiogenesis in the mouse model of oxygen-induced retinopathy. Conclusions—: Our findings suggest that IL-37 is a novel and potent proangiogenic cytokine with essential role in pathophy siological settings.

Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53’s tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.