Monocrotaline, an Alternative to Retrorsine-Based Hepatocyte Transplantation in Rodents

Abstract

Retrorsine has been used extensively to inhibit proliferation of resident hepatocytes in various transplantation models. Here we report a successful alternative to currently unavailable retrorsine that can be used in cellular transplantation models. Based on structural and molecular similarities, we investigate the use of monocrotaline (MCT) in cell transplantation studies in rodents. In this study, MCT was given to rats intraperitoneally in two injections 2 weeks apart. Two weeks after the final injection, a partial hepatectomy followed by splenic hepatocyte transplantation was performed. The results indicate that MCT, at two doses of 30 mg/kg, highly enhances liver repopulation by donor hepatocytes following partial hepatectomy and produces 15.3 +/- 4.9% liver repopulation within the first 6 weeks following transplantation. Additionally, we tested the effectiveness of MCT in a murine model. Using two injections of 50 mg/kg each, given 2 weeks apart, hepatocyte proliferation in the native liver was inhibited and subsequent oval cell transplants engrafted at 18 +/- 21.3% after 16 weeks posttransplantation. In conclusion, MCT can be used as an effective selective pressure for donor hepatocytes in cell transplantation to the liver in rodents.

Noninvasive Imaging of Liver Repopulation following Hepatocyte Transplantation

“…This events in intact living mammals is an active area of current research (36 for liver repopulation (7,34). Chowdhury, J.; Hetherington, H. P.; Guha, C. Noninvasive evaluation of liver repopulation by transplanted hepa-…”

Transplanted endothelial cells repopulate the liver endothelium and correct the phenotype of hemophilia A mice

“…Alternatively, we administered a genotoxic pyrrolizidine alkaloid, monocrotaline (MCT), which disrupts the sinusoidal endothelial barrier and facilitates incor- poration of transplanted hepatocytes into the liver parenchyma (17)(18)(19). The rationale of this latter approach was based on the fact that MCT is a potent toxin to ECs and causes widespread disruption of endothelia in intact animals (20,21).…”

Regional Transient Portal Ischemia and Irradiation as Preparative Regimen for Hepatocyte Transplantation

“…The portal branches of the right superior anterior and right liver cable in clinical settings (15,19,40). Hence, novel concepts of liver repopulation have to be established, utilizlobules 1-3 (45% of liver mass) were isolated and occluded with a Yasargil clamp (Fig.…”