Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells.

Abstract

Reconstitution of healthy endothelial cells in vascular beds offers opportunities for mechanisms in tissue homeostasis, organ regeneration, and correction of deficient functions. Liver sinusoidal endothelial cells express unique functions, and their transplantation is relevant for disease models and for cell therapy. As molecular targets for improving transplanted cell engraftment and proliferation will be highly significant, this study determined whether ETA/B receptor antagonism by the drug bosentan could overcome cell losses due to cell transplantation-induced cytotoxicity. Cell engraftment and proliferation assays were performed with healthy wild-type liver sinusoidal endothelial cells transplanted into the liver of dipeptidylpeptidase IV knockout mice. Transplanted cells were identified in tissues by enzyme histochemistry. Cells with prospective ETA/B antagonism engrafted significantly better in hepatic sinusoids. Moreover, these cells underwent multiple rounds of division under liver repopulation conditions. The gains of ETA/B antagonism resulted from benefits in cell viability and membrane integrity. Also, in bosentan-treated cells, mitochondrial homeostasis was better maintained with less oxidative stress and DNA damage after injuries. Intracellular effects of ETA/B antagonism were transduced by conservation of ataxia telangiectasia mutated protein, which directs DNA damage response. Therefore, ETA/B antagonism in donor cells will advance vascular reconstitution. Extensive experience with ETA/B antagonists will facilitate translation in people.