AIMS: Therapeutic replacement of organs with healthy cells requires disease-specific strategies. As copper toxicosis due to ATP7B deficiency in Wilson disease produces significant liver injury, disease-specific study of transplanted cell proliferation will offer insights into cell and gene therapy mechanisms. MATERIALS & METHODS: We used Long-Evans Cinnamon (LEC) rats to demonstrate the effects of liver preconditioning with radiation and ischemia reperfusion, followed by transplantation of healthy Long-Evans Agouti rat hepatocytes and analysis of hepatic atp7b mRNA, bile copper, liver copper and liver histology. RESULTS: LEC rats without cell therapy or after transplantation of healthy cells without liver conditioning accumulated copper and showed liver disease during the study period. Liver conditioning incorporating hepatic radiation promoted transplanted cell proliferation and reversed Wilson disease parameters, although with interindividual variations and time lags for improvement, which were different from previous results of liver repopulation in healthy animals. CONCLUSION: Cell therapy will correct genetic disorders characterized by organ damage. However, suitable mechanisms for inducing transplanted cell proliferation will be critical for therapeutic success.
AIMS: Therapeutic replacement of organs with healthy cells requires disease-specific strategies. As copper toxicosis due to ATP7Bdeficiency in Wilson disease produces significant liver injury, disease-specific study of transplanted cell proliferation will offer insights into cell and gene therapy mechanisms. MATERIALS & METHODS: We used Long-Evans Cinnamon (LEC) rats to demonstrate the effects of liver preconditioning with radiation and ischemia reperfusion, followed by transplantation of healthy Long-Evans Agouti rat hepatocytes and analysis of hepatic atp7b mRNA, bile copper, liver copper and liver histology. RESULTS: LEC rats without cell therapy or after transplantation of healthy cells without liver conditioning accumulated copper and showed liver disease during the study period. Liver conditioning incorporating hepatic radiation promoted transplanted cell proliferation and reversed Wilson disease parameters, although with interindividual variations and time lags for improvement, which were different from previous results of liver repopulation in healthy animals. CONCLUSION: Cell therapy will correct genetic disorders characterized by organ damage. However, suitable mechanisms for inducing transplanted cell proliferation will be critical for therapeutic success.
Authors: Marc Benderitter; Fabio Caviggioli; Alain Chapel; Robert P Coppes; Chandan Guha; Marco Klinger; Olivier Malard; Fiona Stewart; Radia Tamarat; Peter van Luijk; Charles L Limoli Journal: Antioxid Redox Signal Date: 2014-02-03 Impact factor: 8.401