Integrin and extracellular matrix interactions regulate engraftment of transplanted hepatocytes in the rat liver.
OBJECTIVE
Recognition and circumvention of the hepatic endothelial barrier is critical in the engraftment of transplanted cells. We examined whether interactions between integrin and extracellular matrix component receptors could be manipulated for improving transplanted cell engraftment and liver repopulation.


METHODS
Fischer 344 rat hepatocytes were transplanted into syngeneic dipeptidyl peptidase IV-deficient rats. Coating of cells or of liver sinusoids with natural collagen, natural laminin, or an engineered fibronectin-like polymer was studied with analysis of cell engraftment and liver repopulation using histologic and molecular assays. Focal adhesion complexes were identified by vinculin immunostaining. The role of integrin receptors in cell engraftment was analyzed with RGD peptide inhibition assays.


RESULTS
Coating of cells with extracellular matrix components before transplantation did not enhance cell engraftment. In contrast, intraportal infusion of collagen or fibronectin-like polymer in recipients prior to cell transplantation increased cell engraftment. Adherence of transplanted cells to the hepatic endothelium resulted in rapid activation of vinculin-containing focal adhesion complexes. Superior cell engraftment in animals treated with fibronectin-like polymer was RGD sensitive, verifying the integrin-dependent nature of this process. Moreover, studies in the retrorsine-partial hepatectomy rat model showed that intraportal infusion of the fibronectin-like polymer before cell transplantation significantly accelerated liver repopulation.


CONCLUSIONS
Integrin-extracellular matrix component interactions can be manipulated for enhancing cell engraftment in the liver. Such mechanisms will be relevant for engraftment of other cell types and for strategies concerning liver-directed cell therapy.
Kumaran
Vinay
V
Department of Medicine, Marion Bessin Liver Research Center, Cancer Research Center, Diabetes Research Center, and General Clinical Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Joseph
Brigid
B
Benten
Daniel
D
Gupta
Sanjeev
S
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D006085:Graft Survival / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000637:transplantation*; D016023:Integrins / Q000378:metabolism*; D007700:Kinetics; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains
D016023:Integrins; D018819:Dipeptidyl Peptidase 4