Potential utility of xenobiotic mitogens in the context of liver regeneration in the elderly and living-related transplantation

Abstract

Although liver regeneration occurring after partial hepatectomy (PH) is greatly reduced in aged mice, liver hyperplasia induced by xenobiotic mitogens was found to be age independent. Here, we investigated the potential utility of mitogens in stimulating liver regeneration in old mice subjected to two-third PH. Although virtually no hepatocytes entered S phase 48 h after PH, pretreatment (2 h prior to surgery) with 1,4-bis(2-(3,5-dichloropyridyloxy)benzene (TCPOBOP), a ligand of constitutive androstane receptor, induced an increase of bromodeoxyuridine incorporation and enhanced the expression of cyclin D1, cyclin A and proliferating cell nuclear antigen . Next, we investigated the potential utility of mitogens in the context of donor conditioning prior to living-related transplantation. Three days after TCPOBOP administration to intact young mice, an almost doubling of the liver mass and DNA content occurred; the regenerative response to two-third resection of the TCPOBOP-induced hyperplastic liver was similar to that of mice subjected to PH alone, suggesting that an increased liver mass at the time of surgery does not inhibit the regenerative capacity. The present results suggest that mitogen-induced hyperplasia is a promising tool in conditions characterized by reduced regenerative capacity, such as in the elderly, or when a rapid increase of liver mass is required, such as in living-related transplantation.

Global gene expression profile of normal and regenerating liver in young and old mice

“…Therefore, we investigated whether the enhanced YAP expression observed in the liver of old mice is the result of mechanisms that Bsense^the decreased liver mass and signal a proliferative response in an attempt to re-establish the original organ size. To better understand whether liver size dictates YAP expression, we evaluated its protein content in young mice subjected to surgery after induction of hepatomegaly by treatment with the hepatomitogen TCPOBOP (Columbano et al 2008). Animals were sacrificed 72 h after PH, since under this condition, hepatic mass reaches the values of the liver of intact animals within 3 days (Columbano et al 2008).…”

“…To better understand whether liver size dictates YAP expression, we evaluated its protein content in young mice subjected to surgery after induction of hepatomegaly by treatment with the hepatomitogen TCPOBOP (Columbano et al 2008). Animals were sacrificed 72 h after PH, since under this condition, hepatic mass reaches the values of the liver of intact animals within 3 days (Columbano et al 2008). As shown in Fig.…”

1,4‐Bis[2‐(3,5‐dichloropyridyloxy)]benzene induces substantial hyperplasia in fibrotic mouse liver

“…For this purpose we chose to induce liver fibrosis using two standard protocols. The upregulation of CYP2b10, a target gene of TCPOBOP’s receptor, CAR (Columbano et al. 2008) indicated that there was an intact signal transduction pathway, although the induction was less intense in cirrhotic liver.…”

“…2006). The decreased regenerative response of liver in aged mice was also explained by increased p27 expression (Columbano et al. 2008).…”

“…These widely disparate regulatory pathways may explain that although the regenerative response of liver is reduced substantially in older animals, no such depression has been seen in the hyperplasia induced by the primary hepatocyte mitogen, TCPOBOP (Ledda‐Columbano et al. 2004; Columbano et al. 2008).…”