Aging is associated with a loss of proliferative capacity of many cell types. In the liver, a reduced and delayed regenerative capacity has been shown in rodents after 2/3 PH, suggesting that “old hepatocytes” have lost the capacity to respond to regenerative stimuli. However, whether the impaired liver regeneration is really due to an intrinsic defect of “old hepatocytes”, or to a lack of availability of factors, such as cytokines and growth factors that are an essential prerequisite for hepatocyte division following cell loss, it is unknown. The aims of our research are to investigate whether: 1) nuclear receptors stimulate an efficient hepatocyte proliferation in the elderly, and ii). nuclear receptors could rescue defective liver regeneration?. This study may have a potential therapeutic relevance as it may suggest a possible use of drugs capable to increase the proliferative response of hepatocytes during transplantation and in gene therapy.

Monica Pibiri has been Research Associate of Pathology since November 2001. Prior to that she was a Post-doc at the Department of Toxicology at the University of Cagliari (1996-2002). In November 2000 she obtained the Specialization in Clinical Pathology at the University of Sassari. From 2000 to 2002 she had a fellowship (2000-2002) from Fondazione italiana Ricerca sul Cancro (FIRC).

G.M Ledda-Columbano, M Pibiri, R. Loi, A. Perra, H. Shinozuka, A. Columbano Early increase in cyclin D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen TCPOBOP. American Journal of Pathology, 156 (1):91-97, 2000.
M. Pibiri, G. M. Ledda-Columbano, C. Cossu, G. Simbula, M. Menegazzi, H. Shinozuka, A. Columbano Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3). FASEB JOURNAL, 15 (6):1006-1012, 2001.
A. Columbano, G.M. Ledda-Columbano, M. Pibiri, D. Concas, J.K. Reddy, M.S. Rao Peroxisome proliferator activated receptor-alpha -/- mice show enhanced hepatocyte proliferation in response to the hepatomitogen 1,4-bis [2-(3,5-dichloropyridyloxy)]benzene, a ligand of constitutive androstane receptor. Hepatology,34:262-266, 2001.
G.M. Ledda-Columbano, M. Pibiri, D. Concas, C. Cossu, M. Tripodi, A. Columbano. Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli. Hepathology, 36:1098-1105, 2002.
G.M. Ledda-Columbano, M. Pibiri, D. Concas, F. Molotzu, G. Simbula, C.Cossu and A. Columbano. Sex difference in the proliferative response of mouse hepatocytes to treatment with the CAR ligand, TCPOBOP. Carcinogenesis,Vol 24, 7: 1-7, 2003.
Ledda-Columbano GM, Pibiri M., Cossu C., Molotzu F, Locker J., Columbano A. Aging does not reduce the hepatocyte proliferative response of mice to the primary mitogen TCPOBOP. Hepatology, 40 (4): 981-8, Oct, 2004.
A Columbano, G.M. Ledda-Columbano, M. Pibiri, C. Cossu, M. Menagazzi, D.D. Moore, W. Huang, J. Tian and J. Locker. GADD45ß is induced through a CAR-dependent TNF-independent pathway in murine liver hyperplasia. Hepatology, 42, 1118-1126, 2005.
Simbula G, Columbano A, Ledda-Columbano GM, Sanna L, Deidda M, Diana A, Pibiri M. Increased ROS generation and p53 activation in alpha-lipoic acid-induced apoptosis of hepatoma cells. Apoptosis. Jan;12(1):113-23, 2007.
Perra A, Pibiri M, Sulas P, Simbula G, ledda-Columbano GM, Columbano A. {alpha}-Lipoic acid promotes the growth of rat hepatic preneoplastic lesions in the coline-deficient model. Carcinogenesis, 2007 in press
Columbano A, Simbula M, Pibiri M, Perra A, Deidda M, Locker J, Pisanu A, Uccheddu A, Ledda-Columbano GM. Triiodothyronine stimulates hepatocyte proliferation in two models of impaired liver regeneration. Cell Proliferation, 2008 in press
Columbano A, Simbula M, Pibiri M, Perra A, Pisanu A, Uccheddu A, Ledda-Columbano GM. Potential utility of xenobiotic mitogens in the context of liver regeneration in the elderly and living-related transplantation. Lab Investigation, 2008 in press