The epigenetic mechanism of mechanically induced osteogenic differentiation

Arnsdorf, Emily J.; Tummala, Padmaja; Castillo, Alesha B.; Zhang, Fan; Jacobs, Christopher R.

doi:10.1016/j.jbiomech.2010.07.033

« Previous Next »Journal of Biomechanics
Volume 43, Issue 15 , Pages 2881-2886, 16 November 2010

The epigenetic mechanism of mechanically induced osteogenic differentiation

Emily J. Arnsdorf
- Bone and Joint Rehabilitation R&D Center, VA Palo Alto Medical Center, Palo Alto, CA, United States
- Stanford University, Department of Bioengineering, Stanford, CA, United States
Padmaja Tummala
- Bone and Joint Rehabilitation R&D Center, VA Palo Alto Medical Center, Palo Alto, CA, United States
Alesha B. Castillo
- Bone and Joint Rehabilitation R&D Center, VA Palo Alto Medical Center, Palo Alto, CA, United States
- Stanford University, Department of Mechanical Engineering, Stanford, CA, United States
Fan Zhang
- Stanford University, Departments of Microbiology and Immunology, Stanford, CA,, United States
Christopher R. Jacobs
- Bone and Joint Rehabilitation R&D Center, VA Palo Alto Medical Center, Palo Alto, CA, United States
- Stanford University, Department of Bioengineering, Stanford, CA, United States
- Stanford University, Department of Mechanical Engineering, Stanford, CA, United States
- Columbia University, Department of Biomedical Engineering, NY, NY, United States
- Corresponding author at: 351 Engineering Terrace, Department of Biomedical Engineering, Columbia University, NY 10027, NY, United States. Tel.: +12128510271.

Accepted 21 July 2010. published online 23 August 2010.

Abstract

Epigenetic regulation of gene expression occurs due to alterations in chromatin proteins that do not change DNA sequence, but alter the chromatin architecture and the accessibility of genes, resulting in changes to gene expression that are preserved during cell division. Through this process genes are switched on or off in a more durable fashion than other transient mechanisms of gene regulation, such as transcription factors. Thus, epigenetics is central to cellular differentiation and stem cell linage commitment. One such mechanism is DNA methylation, which is associated with gene silencing and is involved in a cell’s progression towards a specific fate. Mechanical signals are a crucial regulator of stem cell behavior and important in tissue differentiation; however, there has been no demonstration of a mechanism whereby mechanics can affect gene regulation at the epigenetic level. In this study, we identified candidate DNA methylation sites in the promoter regions of three osteogenic genes from bone marrow derived mesenchymal stem cells (MSCs). We demonstrate that mechanical stimulation alters their epigenetic state by reducing DNA methylation and show an associated increase in expression. We contrast these results with biochemically induced differentiation and distinguish expression changes associated with durable epigenetic regulation from those likely to be due to transient changes in regulation. This is an important advance in stem cell mechanobiology as it is the first demonstration of a mechanism by which the mechanical micro-environment is able to induce epigenetic changes that control osteogenic cell fate, and that can be passed to daughter cells. This is a first step to understanding that will be vital to successful bone tissue engineering and regenerative medicine, where continued expression of a desired long-term phenotype is crucial.

Keywords: Mesenchymal stem cell, Osteogenic differentiation, Mechanotransduction, Epigenetic