Sustained perfusion of revascularized bioengineered livers heterotopically transplanted into immunosuppressed pigs

• Published in: Nature biomedical engineering Vol. 4; no. 4; pp. 437 - 445
• Main Authors: Shaheen, Mohammed F, Joo, Dong Jin, Ross, Jeffrey J, Anderson, Brett D, Chen, Harvey S, Huebert, Robert C, Li, Yi, Amiot, Bruce, Young, Anne, Zlochiver, Viviana, Nelson, Erek, Mounajjed, Taofic, Dietz, Allan B, Michalak, Gregory, Steiner, Benjamin G, Davidow, Dominique Seetapun, Paradise, Christopher R, van Wijnen, Andre J, Shah, Vijay H, Liu, Mengfei, Nyberg, Scott L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2020
• Subjects: Animals; Bioengineering; Biomedical engineering; Biomedical Engineering - methods; Bioreactors; Cell Culture Techniques - instrumentation; Cell Culture Techniques - methods; Cell growth; Collagen; Endothelial Cells; Gene expression; Glucose; Histamine; Humans; Immune response; Immunosuppression; Immunosuppression Therapy; Implantation; Kinetics; Liver; Liver - immunology; Liver Transplantation - methods; Perfusion; Perfusion - instrumentation; Perfusion - methods; Sine waves; Spleen; Splenectomy; Steroids; Swine; Thrombosis; Tissue Scaffolds; Transplantation, Heterotopic - methods; Transplants & implants; Umbilical vein; Vascular Patency; Veins & arteries
• ISSN: 2157-846X; 2157-846X
• DOI: 10.1038/s41551-019-0460-x

Implanted bioengineered livers have not exceeded three days of continuous perfusion. Here we show that decellularized whole porcine livers revascularized with human umbilical vein endothelial cells and implanted heterotopically into immunosuppressed pigs whose spleens had been removed can sustain perfusion for up to 15 days. We identified peak glucose consumption rate as a main predictor of the patency of the revascularized bioengineered livers (rBELs). Heterotopic implantation of rBELs into pigs in the absence of anticoagulation therapy led to sustained perfusion for three days, followed by a pronounced immune responses directed against the human endothelial cells. A 10 day steroid-based immunosuppression protocol and a splenectomy at the time of rBEL implantation reduced the immune responses and resulted in continuous perfusion of the rBELs for over two weeks. We also show that the human endothelial cells in the perfused rBELs colonize the liver sinusoids and express sinusoidal endothelial markers similar to those in normal liver tissue. Revascularized liver scaffolds that can maintain blood perfusion at physiological pressures might eventually help to overcome the chronic shortage of transplantable human livers.