Gavin J. Gordon, Ph.D.

Dissertation research performed under the guidence of William B. Coleman

ABSTRACT
   The adult rodent liver contains at least two populations of cells with stem-like properties which contribute to liver repair/regeneration under different pathophysiologic circumstances: (i) unipotential committed progenitor cells (hepatocytes and biliary epithelial cells) and (ii) multipotential nonparenchymal progenitor cells (oval cells).  In retrorsine-induced hepatocellular injury the capacity of fully-differentiated rat hepatocytes to replicate is severely impaired and massive proliferation of oval cells does not occur.  Nevertheless, retrorsine-exposed rats can replace their entire liver mass after surgical partial hepatectomy through the emergence and rapid expansion of a population of small, incompletely-differentiated hepatocyte-like progenitor cells (SHPCs) that express phenotypic characteristics of fetal hepatoblasts, oval cells, and fully-differentiated hepatocytes, but differ distinctly from each.  The activation, proliferation, and complete regeneration of normal liver structure from SHPCs has not been recognized in other models of chemical liver injury characterized by impaired hepatocyte replication.  Isolated SHPCs resemble their in vivo counterparts in appearance and are amenable to culture under certain conditions.  Conditions have not yet been identified that facilitate SHPC expansion in vitro even though these cells display a hepatocyte-like phenotype and are able to persist up to several weeks in culture.  The progeny of transplanted (DPPIV-positive) SHPCs can be detected in the livers of syngeneic (DPPIV-negative) host rats after transplantation.  SHPC progeny engraft into the hepatic plate, are properly polarized, form bile canaliculi contiguous with those of host hepatocytes, and are indistinguishable from surrounding host hepatocytes in appearance and phenotype (except for expression of DPPIV marker enzyme).  Furthermore, the progeny of transplanted SHPCs can undergo moderate proliferation in response to the growth stimulus of PH (similar to host hepatocytes).  The results of the studies contained within this dissertation strongly suggest that SHPCs represent a novel hepatic progenitor cell population that (i) responds to liver deficit when the replication capacity of differentiated hepatocytes is impaired, (ii) expresses an extensive proliferative capacity, (iii) can give rise to large numbers of progeny hepatocytes, (iv) can restore tissue mass, (v) can be maintained in culture under certain conditions, and (vi) can be transplanted into the livers of host rats and give rise to cells displaying a hepatocyte-specific phenotype.