Research Article

The effects of DNA methyltransferase inhibitors and histone deacetylase inhibitors on digit regeneration in mice

Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.

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Email the corresponding author at ljgudas@med.cornell.edu

Stephen F Badylak

McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA

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Ellen Heber-Katz

The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA

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Susan J Braunhut

Department of Biological Sciences, University of Massachusetts–Lowell, Lowell, MA 01854, USA

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Lorraine J Gudas

† Author for correspondence

Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.

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Email the corresponding author at ljgudas@med.cornell.edu

Published Online:8 Mar 2010https://doi.org/10.2217/rme.09.91

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Abstract

Method: We injected two drugs that modify the epigenome, the DNA methyltransferase inhibitor 5-aza-2´-deoxycytidine (5-aza-dC) and the histone deacetylase inhibitor trichostatin A (TSA), alone or in combination, into C57Bl/6 mice subjected to amputation through the mid-second phalanx of the third digit. Wound-site tissue was collected. Results: We observed increased staining of the stem cell markers Rex1 (Zfp42) and stem cell antigen-1 at digit amputation sites from drug-treated mice. Samples from 5-aza-dC plus TSA and TSA treated mice also showed increased proliferating cell nuclear antigen staining, a measure of cell proliferation. Drug treatments increased Msx1, but not Cyp26a1 or ALDH1a2 (RALDH2) mRNA. Conclusion: 5-aza-dC and TSA treatments stimulated cell proliferation at the amputation site, possibly via increased expression of genes involved in digit development and regeneration.

Keywords:

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Acknowledgements

The authors are grateful for the insightful scientific input provided by the members of the Gudas laboratory and to Leiping Fu for providing Msx1 primers, Limin Liu for providing Cyp26a1 primers, Kristian B Laursen for providing Bmp4 primers and Mary Ng, Xiao-Han Tang, Marty Albert and Christopher Kelly for experimental and editorial assistance. The authors thank Jon Mogford (DARPA) for useful scientific suggestions with respect to these experiments.

Financial & competing interests disclosure

This research was supported by a DOD/DARPA Mammalian Limb Restoration Grant UPIT W911NF 06–1–0067 awarded to Lorraine J Gudas. This was a sub-grant via the University of Pittsburgh, in which Stephen F Badylak was the overall program project PI. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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