Epigenetic approaches: the emerging role of histone deacetylase inhibitors (HDACis) in promoting dental pulp cell repair mechanisms in vitro

Duncan, Hal Fergus (2017). Epigenetic approaches: the emerging role of histone deacetylase inhibitors (HDACis) in promoting dental pulp cell repair mechanisms in vitro. University of Birmingham. Ph.D.

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Abstract

Despite recent improvements in the clinical outcomes of vital pulp treatment, existing approaches remain non-specific and unpredictable. Developing biologically-based therapies that promote pulp regeneration is critical. Epigenetic modifications of DNA and histones control cellular processes, including proliferation, mineralisation and stem cell fate, and therefore offer exciting therapeutic opportunities. Chromatin acetylation can be altered pharmacologically using histone-deacetylase-inhibitors (HDACis), which relax its structure and modulate transcription. This project investigated regenerative-associated HDACi effects in vitro on a cell-line and primary dental-pulp-cells (DPCs), using proliferation, viability, mineralisation, cell-migration, enzyme activity, high-throughput gene/protein expression and pathway analyses. HDACis increased DPC differentiation and mineralisation-associated gene/protein expression at concentrations, which did not reduce viability. Primary DPC mineralisation was promoted without altering cell viability/apoptosis, indicating a resistance to HDACi-mediated toxicity compared with cell-lines. HDACi-induced DPC reparative processes were mediated by matrix metalloproteinase (MMP) expression and activity. MMP-13 inhibition further increased mineralisation-associated events, but decreased cell-migration indicating a novel role for MMP-13 in pulpal repair. HDACi solutions released a range of previously characterised and unreported bioactive dentine matrix components, which may further supplement regenerative capability in vivo. Results demonstrate that HDACi directly stimulate DPC repair-associated events, highlighting their potential for augmenting dental materials or pulp-engineering scaffolds for regenerative endodontics.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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