L-mimosine and hypoxia can increase angiogenin production in dental pulp-derived cells

Janjić, Klara; Edelmayer, Michael; Moritz, Andreas; Agis, Hermann

doi:10.1186/s12903-017-0373-6

Cited by 16 publications

(23 citation statements)

References 45 publications

(52 reference statements)

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“…ANG is required for cell proliferation induced by various other angiogenic factors, including VEGF (19). Hypoxia increases ANG production in human malignant melanoma cells (20) and human dental pulp-derived cells (21). The present study is the first to show that hPDLF responds to hypoxia by increasing production of ANG and VEGF and that HIF-1α has a pivotal role in activating ANG and VEGF production under hypoxic conditions.…”

Section: Discussionmentioning

confidence: 50%

Hypoxia-induced upregulation of angiogenic factors in immortalized human periodontal ligament fibroblasts

et al. 2018

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Hypoxia induces complex cellular responses that are mediated by a key transcription factor, hypoxia-inducible factor-1 (HIF-1). HIF-1 promotes production of cytokines and angiogenic factors and contributes to recovery of injured tissues. In the present study, expressions of angiogenin (ANG) and vascular endothelial growth factor (VEGF), which are potent angiogenic factors in mammalian tissues, were examined in immortalized fibroblasts exposed to hypoxia. After 24 h of exposure to hypoxia, ANG and VEGF mRNAs expressions were significantly elevated in periodontal ligament (PDL) fibroblasts but not in embryonic fibroblasts. Hypoxia also increased productions of ANG and VEGF proteins in PDL fibroblasts. HIF-1α mRNA expression was not affected by hypoxia in either fibroblast, although HIF-1α protein expression was enhanced after exposure to hypoxia. Treatment of PDL fibroblasts with dimethyloxaloylglycine, a prolyl hydroxylase inhibitor that stabilizes the HIF-1α protein, significantly increased expressions of ANG and VEGF mRNAs under normoxia. This suggests that stabilization of HIF-1α is crucial for upregulation of ANG and VEGF in PDL fibroblasts. These results indicate that, under hypoxic conditions, HIF-1α upregulates synthesis of ANG and VEGF in PDL fibroblasts and promotes angiogenesis.

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Section: Discussionmentioning

confidence: 50%

Hypoxia-induced upregulation of angiogenic factors in immortalized human periodontal ligament fibroblasts

et al. 2018

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“…Considering this, it was interesting to investigate whether DPC self-assembled into stable rod-shaped terminal structures. Spheroid-shaped microtissues of DPC have been established as terminal structures [25,26] for endodontic regenerative strategies. Their property of self-aggregation makes intimate cell-cell communication and cell-extracellular matrix interaction possible by forming an in vivo-like extracellular matrix [27].…”

Section: Discussionmentioning

confidence: 99%

Contraction dynamics of dental pulp cell rod microtissues

et al. 2019

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Objectives The factors that contribute to the morphological changes of dental pulp cell-derived microtissues are unknown. Here, we investigated the contraction dynamics of rod-shaped microtissues derived from dental pulp cells and examined the underlying cell signaling pathways. Methods Human dental pulp cells were seeded into agarose molds to assemble into rod-shaped microtissues. Resazurin-and tetrazolium-based cytotoxicity assays, Live/Dead staining, and hematoxylin and eosin staining for histological evaluation of rods were performed. Rod contraction was evaluated and measured for a period of 10 days. The role of TGF-β, phosphoinositide 3kinase (PI3K)/AKT, and mitogen-activated protein kinase (MAPK) signaling pathway was analyzed. Results Dental pulp cells readily assembled into rods, maintaining the geometric shape for 48 h. Following this period, they condensed to form stable spheroidal structures that remained vital for 10 days from seeding. Inhibition of phosphoinositide 3kinase signaling pathway by LY294002 significantly prolonged the diminution in the length of rods formed by dental pulp cells. TGF-β and pharmacological inhibition of TGF-β signaling did not show pronounced effects. Conclusion Overall, dental pulp cells readily formed rod-shaped patterns of microtissues which, over a period of time, condensed into more stable spheroidal structures. Hence, technologies like bioprinting, using direct fabrication of microtissues need to consider the contraction dynamics. Clinical relevance The field of regenerative endodontology will benefit from our findings as it can be applied as a novel platform to test the impact of pharmacological agents, biomaterials, and regenerative approaches including bioprinting.

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“…The conditions were based on preliminary unpublished experiments and previous in vitro studies . To establish hypoxic conditions we used an established protocol with minor modifications . The culture plates were placed into BD GasPak EZ Pouches (Becton, Dickinson and Company, Franklin Lakes, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

“…27,28 To establish hypoxic conditions we used an established protocol with minor modifications. [29][30][31] The culture plates were placed into BD GasPak EZ Pouches (Becton, Dickinson and Company, Franklin Lakes, NJ, USA). The manufacturer confirms that the oxygen concentration rapidly decreases to a level of <1%.…”

Section: Monolayer Culturementioning

confidence: 99%

Angiopoietin‐like 4 production upon treatment with hypoxia and L‐mimosine in periodontal fibroblasts

Janjić

Schellner

Engenhart

et al. 2019

J of Periodontal Research

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Background and objective A key factor in the modulation of angiogenesis as well as in bone resorption is angiopoietin‐like 4. However, the role of angiopoietin‐like 4 in periodontal tissue is unknown. Here, we hypothesized that hypoxia and the hypoxia mimetic agent L‐mimosine can induce the production of angiopoietin‐like 4 in periodontal fibroblasts. Methods Human periodontal ligament fibroblasts (PDLF) were cultured in monolayer and spheroid cultures. The cultures were incubated in the presence of hypoxia or L‐mimosine. Angiopoietin‐like 4 mRNA and protein levels were measured by qPCR and ELISA, respectively. Also, the impact of Lipopolysaccharides of E. coli and P. gingivalis, interleukin (IL)‐1β and tumor necrosis factor (TNF)α was evaluated. Furthermore, we tested dependency on hypoxia‐inducible factor (HIF)‐1 activity by Western blotting for HIF‐1 and inhibitor studies with echinomycin. Potential autocrine effects were assessed by exposure of PDLF to recombinant angiopoietin‐like 4 in full length, C‐terminal and N‐terminal fragments. The impact on viability, DNA synthesis, alkaline phosphatase, and matrix mineralization was evaluated. Results Both hypoxia and L‐mimosine elevated angiopoietin‐like 4 mRNA and protein levels in monolayer cultures of PDLF. HIF‐1 was elevated after both hypoxia and L‐mimosine treatment. LPS, IL‐1β, and TNFα did not modulate angiopoietin‐like 4 levels significantly. Addition of echinomycin in the cultures inhibited the production of angiopoietin‐like 4. In spheroid cultures of PDLF, the increase did not reach the level of significance at mRNA and protein levels. Angiopoietin‐like 4 in full length, C‐terminal, and N‐terminal fragments did not modulate viability, DNA synthesis, alkaline phosphatase, and matrix mineralization. Conclusion Overall, we found that hypoxia and the hypoxia mimetic agent L‐mimosine can stimulate angiopoietin‐like 4 production in monolayer cultures of PDLF. This increase depends on HIF‐1 activity. Future studies will reveal how the modulation of angiopoietin‐like 4 in the periodontium contributes to periodontal disease and regeneration.

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L-mimosine and hypoxia can increase angiogenin production in dental pulp-derived cells

Cited by 16 publications

References 45 publications

Hypoxia-induced upregulation of angiogenic factors in immortalized human periodontal ligament fibroblasts

Hypoxia-induced upregulation of angiogenic factors in immortalized human periodontal ligament fibroblasts

Contraction dynamics of dental pulp cell rod microtissues

Angiopoietin‐like 4 production upon treatment with hypoxia and L‐mimosine in periodontal fibroblasts

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