Transplanted hepatocytes proliferate differently after CCl₄treatment and hepatocyte growth factor infusion

Abstract

To understand regulation of transplanted hepatocyte proliferation in the normal liver, we used genetically marked rat or mouse cells. Hosts were subjected to liver injury by carbon tetrachloride (CCl4), to liver regeneration by a two-thirds partial hepatectomy, and to hepatocellular DNA synthesis by infusion of hepatocyte growth factor for comparative analysis. Transplanted hepatocytes were documented to integrate in periportal areas of the liver. In response to CCl4 treatments after cell transplantation, the transplanted hepatocyte mass increased incrementally, with the kinetics and magnitude of DNA synthesis being similar to those of host hepatocytes. In contrast, when cells were transplanted 24 h after CCl4 administration, transplanted hepatocytes appeared to be injured and most cells were rapidly cleared. When hepatocyte growth factor was infused into the portal circulation either subsequent to or before cell transplantation and engraftment, transplanted cell mass did not increase, although DNA synthesis rates increased in cultured primary hepatocytes as well as in intact mouse and rat livers. These data suggested that procedures causing selective ablation of host hepatocytes will be most effective in inducing transplanted cell proliferation in the normal liver. The number of transplanted hepatocytes was not increased in the liver by hepatocyte growth factor administration. Repopulation of the liver with genetically marked hepatocytes can provide effective reporters for studying liver growth control in the intact animal.

Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia–reperfusion leads to extensive liver repopulation

“…deposits hepatocytes into liver sinusoids (2)(3)(4)(5). The whole liver was radiated to 10-50 Gy with an orthovoltage x-ray machine (Philips Super M 100, Philips Medical Systems, Bothell, WA), as reported (16).…”

Repopulation of Mouse Liver With Human Hepatocytes And In Vivo Infection With Hepatitis B Virus

“…[20][21][22] Previous studies documented that transplanted hepatocytes can integrate into the host liver parenchyma [23][24][25] ; however, transplanted hepatocytes show very limited proliferative activity in the normal liver. 26 Studies in transgenic mice have shown that the liver can be repopulated by genetically engineered rodent hepatocytes harboring a selective growth advantage over resident hepatocytes. [27][28][29][30] The discovery of a liver-toxic phenotype in urokinase-type plasminogen activator (uPA) transgenic mice led to the development of a novel liver repopulation model, in which hepatocyte-targeted expression of the albumin-uPA transgene depletes host hepatocytes progressively.…”

Liver gene therapy: advances and hurdles

“…78 The remaining cells translocated from sinusoids into liver plates within 20 h after cell transplantation, through a process involving disruption of the sinusoidal endothelium, release of vascular endothelial growth factor (VEGF) by both host and transplanted hepatocytes. 77,79,80 Subsequently, translocated cells integrated into the liver parenchyma, regained their polarity with the formation of gap junctions and bile canaliculi between transplanted and host hepatocytes within about 1 week, without any significant proliferation in adult animals and were functional throughout the life of animals. 74,75,81 Overall, only 20-30% of transplanted hepatocytes integrated into the liver.…”

“…Partial hepatectomy and hepatocyte growth factor infusion were ineffective in increasing the transplanted hepatocyte mass, because both transplanted and host hepatocytes had been removed and/or responded equally to the regenerative stimuli. 41,80 In contrast, carbon tetrachloride (CCl 4 ) treatments increased the transplanted hepatocyte mass. 80 This is in agreement with the fact that CCl 4 selectively injured centrolobular hepatocytes, leading to the compensatory proliferation of portal hepatocytes, and that transplanted hepatocytes were mostly located in periportal areas.…”

“…41,80 In contrast, carbon tetrachloride (CCl 4 ) treatments increased the transplanted hepatocyte mass. 80 This is in agreement with the fact that CCl 4 selectively injured centrolobular hepatocytes, leading to the compensatory proliferation of portal hepatocytes, and that transplanted hepatocytes were mostly located in periportal areas. However, host portal hepatocytes also proliferated after CCl 4 treatments, which limited the extent of transplanted hepatocyte expansion.…”