Harnessing the HDAC\u2013histone deacetylase enzymes, inhibitors and how these can be utilised in tissue engineering

Liam Lawlor,Xuebin B Yang

doi:10.1038/s41368-019-0053-2

Abstract

There are large knowledge gaps regarding how to control stem cells growth and differentiation. The limitations of currently available technologies, such as growth factors and/or gene therapies has led to the search of alternatives. We explore here how a cell’s epigenome influences determination of cell type, and potential applications in tissue engineering. A prevalent epigenetic modification is the acetylation of DNA core histone proteins. Acetylation levels heavily influence gene transcription. Histone deacetylase (HDAC) enzymes can remove these acetyl groups, leading to the formation of a condensed and more transcriptionally silenced chromatin. Histone deacetylase inhibitors (HDACis) can inhibit these enzymes, resulting in the increased acetylation of histones, thereby affecting gene expression. There is strong evidence to suggest that HDACis can be utilised in stem cell therapies and tissue engineering, potentially providing novel tools to control stem cell fate. This review introduces the structure/function of HDAC enzymes and their links to different tissue types (specifically bone, cardiac, neural tissues), including the history, current status and future perspectives of using HDACis for stem cell research and tissue engineering, with particular attention paid to how different HDAC isoforms may be integral to this field.

Highlights

There is a largely unmet clinical need for the repair and regeneration of human tissues and organs
This review introduces the structure/function of Histone deacetylase (HDAC) enzymes and their links to different tissue types, including the history, current status and future perspectives of using Histone deacetylase inhibitors (HDACis) for stem cell research and tissue engineering, with particular attention paid to how different HDAC isoforms may be integral to this field
In conclusion, the field of HDACis in tissue engineering is still in its infancy compared with cancer research where at least 4 HDACis have achieved clinical approval, with many others in late-stage clinical trials.[192]

Summary

INTRODUCTION

There is a largely unmet clinical need for the repair and regeneration of human tissues and organs. Research has discovered that modifications to the histone, such as those by histone deacetylation enzymes (HDACs), affect chromatin structure, and stem cell properties such as potency and differentiation.[3,8,9] As such, the epigenetic make-up of a cell may be crucial for cell-based therapies and tissue engineering. HDAC enzymes remove those acetyl groups (histone deacetylation), repressing transcription due to the formation of a more condensed and transcriptionally silenced chromatin.[3] HDAC inhibitors (HDACis) inhibit the action of HDAC enzymes, resulting in increased acetylation levels in the cell This may affect the chromatin compaction, linked to the potency, or differentiation potential of stem cells.[9] Despite the misleading name, containing the word ‘histone’, there are a wide range of non-histone targets of these enzyme.[18]. THE POTENTIAL OF USING HDACIS IN TISSUE ENGINEERING HDACis affect many cellular properties, such as the cell cycle, proliferation rates, gene expression, differentiation potential, International Journal of Oral Science (2019)11:20

HDAC11 Nucleus and cytoplasm193

CONCLUSION