Exploitation of mechanisms regulating hepatic vascular tone for liver repopulation

Transplanted hepatocytes optimally engraft, function and survive in liver plates. We recently demonstrated that size-structure relationships regulate distribution of transplanted hepatocytes within the liver lobule. To define mechanisms by which cells enter the liver lobule, we transplanted hepatocytes expressing dipeptidyl peptidase IV (DPPIV4) into syngeneic DPPFV rats via spleen. This deposited hepatocytes into hepatic sinusoids, although a significant fraction of cells was simultaneously retained within portal vascular spaces. Hepatocytes entering hepatic sinusoids rapidly translocated into host liver plates between 8 hrs and 24 hrs and subsequently survived. However, cells retained in portal vascular spaces did not engraft and were cleared by macrophages. As transplanted hepatocytes were mainly in periportal areas indicating entrapment in proximal sinusoids of the hepatic lobule, we reasoned that modulation of the vascular tone to deposit cells more distally would benefit liver repopulation by decreasing cell retention in portal vein radicles. To examine modulation of cell distributions, rats were given phentolamine (a-blocker), labetalol (a and blocker), nifedipine (Ca++ channel blocker), and glucagon, calcitonin gene-related peptide {CGRP) or nitroglycerine (splanchnic vasodilators). The relative fraction of cells entering hepatic lobules did not change in response to prior labetalol, nifedipine, glucagon or CGRP. However, prior administration of either phentolamine alone or a combination of phentolamine and CGRP resulted in greater cell entry into periportal sinusoids. Prior nitroglycerine infusion proved most effective in depositing cells in hepatic sinusoids distal to portal vascular spaces. Despite increased entry of cells into hepatic sinusoids, however, none of the drugs prevented some cell retention in portal vein radicles. CQNCL USIONS : Pharmacological manipulations will facilitate liver repopulation as cell deposition into specific portions of the liver lobule is regulated by the vascular dimensions of the hepatic inflow tracts. The complex periportal vascular networks in the hepatic lobule with criss-crossing communications between terminal portal venules, hepatic arterioles and sinusoids are amenable to modulation with α-blockade, as well as agents directly affecting the hepatic sinusoidal vascular tone.