A connectivity mapping approach predicted acetylsalicylic acid (aspirin) to induce osteo/odontogenic differentiation of dental pulp cells

Rankin, R.; Lundy, Fionnuala T.; Schock, Bettina; Zhang, S. D.; Al-Natour, Banan; About, Imad; Irwin, Christopher; Linden, Gerard J.; Karim, Ikhlas El

doi:10.1111/iej.13281

Cited by 8 publications

(10 citation statements)

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“…The microarray was carried out on Affymetrix Human Gene 2.1 ST Array (GPL17692) and in order to be compatible with ssCMap, the significantly differentially expressed genes were converted to GPL96 probe IDs as previously described (Rankin et al, 2020). Following conversion, two queries using two gene signatures were created by differential expression analysis, the first query gene signature was generated using significance level cut‐off p = 1/ N ( p = .000018), where N is the total number of probes used in the array, and a second using a significance level cut‐off p = .0001, This cut‐off p ‐value was aimed to control the expected number of false‐positive DEGs.…”

Section: Methodsmentioning

confidence: 99%

“…An ex vivo pulpitis co‐culture model of primary human dental pulp cells (DPCs) and THP‐1 macrophages was set up using a Transwell system (Corning Costar) as previously described (Rankin et al, 2020; Yonehiro et al, 2012). DPCs obtained from three donors were derived by explant culture from third molar teeth as previously described (About et al, 2000; El Karim et al, 2016) and grown in minimal essential medium with L‐glutamine supplemented with 10% Foetal bovine serum (FBS), 100 UI/ml penicillin and 100 mg/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…The technique is employed for drug repositioning approaches (Lamb, 2007) and further developed into the ‘statistically significant connectivity map’ (ssCMap) by using statistical means to control for false connections between gene signature and reference profiles (Musa et al, 2018; Zhang & Gant, 2009). The ssCMap has been successfully applied to phenotypic targeting and predicting effective drugs for several diseases (Malcomson et al, 2016; Ramsey et al, 2013) and recently for induction of osteo/odontogenic phenotypes of dental pulp cells (Rankin et al, 2020). It was therefore hypothesized that connectivity mapping could be used to identify compounds or drugs that could reverse the gene signature in pulpitis from inflammation to a closer to healthy phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Identification and validation of novel biomarkers and therapeutics for pulpitis using connectivity mapping

et al. 2021

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Aim To create an irreversible pulpitis gene signature from microarray data of healthy and inflamed dental pulps, followed by a bioinformatics approach using connectivity mapping to identify therapeutic compounds that could potentially treat pulpitis. Methodology The Gene Expression Omnibus (GEO) database, an international public repository of genomics data sets, was searched for human microarray datasets assessing pulpitis. An irreversible pulpitis gene expression signature was generated by differential expression analysis. The statistically significant connectivity map (ssCMap) method was used to identify compounds with a highly correlating gene expression pattern. qPCR was used to validate novel pulpitis genes. An ex vivo pulpitis model was used to test the effects of the compounds identified, and the level of inflammatory cytokines was measured with qPCR, ELISA and multiplex array. Means were compared using the t‐test or ANOVA with the level of significance set at p ≤ .05. Results Pulpitis gene signatures were created using differential gene expression analysis at cutoff points p = .0001 and .000018. Top upregulated genes were selected as potential pulpitis biomarkers. Among these, IL8, IL6 and MMP9 were previously identified as pulpitis biomarkers. Novel upregulated genes, chemokine (C‐C motif) ligand 21 (CCL21), metallothionein 1H (MT1H) and aquaporin 9 (AQP9) were validated in the pulp tissue of teeth clinically diagnosed with irreversible pulpitis using qPCR. ssCMap analysis identified fluvastatin (Statin) and dequalinium chloride (Quaternary ammonium) as compounds with the strongest correlation to the gene signatures (p = .0001). Fluvastatin reduced IL8, IL6, CCL21, AQP9 (p < .001) and MMP9 (p < .05) in the ex vivo pulpitis model, while dequalinium chloride reduced AQP9 (p < .001) but had no significant effect on the other biomarkers. Conclusions AQP9, MT1H and CCL21 were identified and validated as novel biomarkers for pulpitis. Fluvastatin and dequalinium chloride identified by the ssCMap as potential therapeutics for pulpitis reduced selected pulpitis biomarkers in an ex vivo pulpitis model. In vivo testing of these licenced drugs is warranted.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and validation of novel biomarkers and therapeutics for pulpitis using connectivity mapping

et al. 2021

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“…In DPCs cultured from mouse incisors, NO inhibited cell proliferation in growth culture medium, but promoted mineralisation and apoptosis in mineralisation‐inducing medium (Yasuhara et al, 2007), indicating different roles for DPCs in function of the environment. More recently, an ex vivo 2D model was developed by co‐culturing immortalised or primary human DPCs and macrophages separated by transwells (Rankin et al, 2020; Yonehiro et al, 2012). Co‐culture markedly up‐regulated inflammatory cytokine production as compared with cells cultured independently, suggesting that both cell types interact with each other to produce synergistically high amounts of inflammatory cytokines.…”

Section: Reviewmentioning

confidence: 99%

“…Indeed, fluvastatin and dequalinium chloride identified by ssCMap reduced pulpitis biomarkers and the authors proposed these molecules as potential therapeutic tools (Al‐Natour et al, 2021). A limitation of this study is that the validation of the ssCMap results was only performed in an ex vivo model of 2D co‐culture of DPCs and macrophages (Rankin et al, 2020). Interestingly, different cleaned and normalised microarray databases allowed identifying CD86, FCGR2A, ITGAX and TREM1 messenger RNAs as potential biological biomarkers of pulp inflammation.…”

Section: Reviewmentioning

confidence: 99%

A critical analysis of research methods and experimental models to study pulpitis

et al. 2022

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Pulpitis is the inflammatory response of the dental pulp to a tooth insult, whether it is microbial, chemical, or physical in origin. It is traditionally referred to as reversible or irreversible, a classification for therapeutic purposes that determines the capability of the pulp to heal. Recently, new knowledge about dental pulp physiopathology led to orientate therapeutics towards more frequent preservation of pulp vitality. However, full adoption of these vital pulp therapies by dental practitioners will be achieved only following better understanding of cell and tissue mechanisms involved in pulpitis. The current narrative review aimed to discuss the contribution of the most significant experimental models developed to study pulpitis. Traditionally, in vitro two (2D)‐ or three (3D)‐dimensional cell cultures or in vivo animal models were used to analyse the pulp response to pulpitis inducers at cell, tissue or organ level. In vitro, 2D cell cultures were mainly used to decipher the specific roles of key actors of pulp inflammation such as bacterial by‐products, pro‐inflammatory cytokines, odontoblasts or pulp stem cells. However, these simple models did not reproduce the 3D organisation of the pulp tissue and, with rare exceptions, did not consider interactions between resident cell types. In vitro, tissue/organ‐based models were developed to better reflect the complexity of the pulp structure. Their major disadvantage is that they did not allow the analysis of blood supply and innervation participation. On the contrary, in vivo models have allowed researchers to identify key immune, vascular and nervous actors of pulpitis and to understand their function and interplay in the inflamed pulp. However, inflammation was mainly induced by iatrogenic dentine drilling associated with simple pulp exposure to the oral environment or stimulation by individual bacterial by‐products for short periods. Clearly, these models did not reflect the long and progressive development of dental caries. Lastly, the substantial diversity of the existing models makes experimental data extrapolation to the clinical situation complicated. Therefore, improvement in the design and standardisation of future models, for example by using novel molecular biomarkers, databased models and artificial intelligence, will be an essential step in building an incremental knowledge of pulpitis in the future.

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Endoplasmic reticulum stress response mediated by the PERK-eIF2α-ATF4 pathway is involved in odontoblastic differentiation of human dental pulp cells

Yang

Jiang

et al. 2022

Archives of Oral Biology

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A connectivity mapping approach predicted acetylsalicylic acid (aspirin) to induce osteo/odontogenic differentiation of dental pulp cells

Abstract: Article type : Original Scientific ArticleA connectivity mapping approach predicted acetylsalicylic acid (aspirin) to induce osteo/odontogenic differentiation of dental pulp cells

Cited by 8 publications

References 45 publications

Identification and validation of novel biomarkers and therapeutics for pulpitis using connectivity mapping

Identification and validation of novel biomarkers and therapeutics for pulpitis using connectivity mapping

A critical analysis of research methods and experimental models to study pulpitis

Endoplasmic reticulum stress response mediated by the PERK-eIF2α-ATF4 pathway is involved in odontoblastic differentiation of human dental pulp cells

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