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J. Biol. Chem., Vol. 282, Issue 15, 11197-11204, April 13, 2007

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Restoration of Liver Mass after Injury Requires Proliferative and Not Embryonic Transcriptional Patterns^*

Hasan H. Otu^¶1, Kamila Naxerova^||1, Karen Ho^**2, Handan Can^¶, Nicole Nesbitt^**, Towia A. Libermann, and Seth J. Karp^**3

From the Department of Medicine, Genomics Core, and ^**Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, ^¶Department of Genetics and Bioengineering, Yeditepe University, 34755 Istanbul, Turkey, and ^||Children's Hospital Informatics Program, Boston, Massachusetts 02115

Normal adult liver is uniquely capable of renewal and repair after injury. Whether this response represents simple hyperplasia of various liver elements or requires recapitulation of the genetic program of the developing liver is not known. To study these possibilities, we examined transcriptional programs of adult liver after partial hepatectomy and contrasted these with developing embryonic liver. Principal component analysis demonstrated that the time series of gene expression during liver regeneration does not segregate according to developmental transcription patterns. Gene ontology analysis revealed that liver restoration after hepatectomy and liver development differ dramatically with regard to transcription factors and chromatin structure modification. In contrast, the tissues are similar with regard to proliferation-associated genes. Consistent with these findings, real-time polymerase chain reaction showed transcription factors known to be important in liver development are not induced during liver regeneration. These three lines of evidence suggest that at a transcriptional level restoration of liver mass after injury is best described as hepatocyte hyperplasia and not true regeneration. We speculate this novel pattern of gene expression may underlie the unique capacity of the liver to repair itself after injury.

Received for publication, September 1, 2006 , and in revised form, January 16, 2007.

^* This work was supported in part by National Institutes of Health Grant DK64648 (to S. J. K.) and by the Beth Israel Deaconess Medical Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ Both authors contributed equally to this work.

² Supported by National Institutes of Health Training Grant 2T32HL007734-11.

³ To whom correspondence should be addressed: 110 Francis St., 7th Floor-The Transplant Center, Boston, MA 02215. Tel.: 617-632-9824; Fax: 617-632-9820; E-mail: skarp{at}bidmc.harvard.edu.

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