Delivery of hepatotrophic factors fails to enhance longer-term survival of subcutaneously transplanted hepatocytes.
Tissue engineering approaches have been investigated as a strategy for hepatocyte transplantation; however the death of a majority of transplanted cells critically limits success of these approaches. In a previous study, a transient increase in hepatocyte survival was achieved through delivery of vascular endothelial growth factor (VEGF) from the porous polymer scaffold utilized for cell delivery. To enhance longer-term survival of the hepatocytes, this delivery system was modified to additionally deliver epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in a sustained manner. Hepatocytes were subcutaneously implanted in SCID mice on scaffolds containing EGF and/or HGF, in addition to VEGF, and survival was monitored for two weeks. A short-term enhancement of hepatocyte survival was observed after one week and is attributed to VEGF-enhanced vascularization, which was not altered by EGF or HGF. Surprisingly, long-term hepatocyte engraftment was not improved, as survival declined to the level of control conditions for all growth factor combinations after two weeks. This investigation indicates that the survival of hepatocytes transplanted into heterotopic locations is dependent on multiple signals. The delivery system developed for the current study may be useful in elucidating the specific factors controlling this process, and bring therapeutic transplantation of hepatocytes closer to implementation.
Department of Chemical Engineering, University of Michigan, Ann Arbor, USA.
Molly K
MK
Smith
Kathryn W
KW
Riddle
David J
DJ
Mooney
D000818:Animals; D001672:Biocompatible Materials; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008863:Microspheres; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*
D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor