Liver Regeneration
There are a variety of infectious, neoplastic, metabolic, and autoimmune
disease states which affect the developing liver in the pediatric population.
The unique ability of the liver to regenerate after injury or resection
remains a fascinating yet poorly understood biologic phenomenon, one
with unclear significance to the treatment of pediatric liver disease.
Cell therapy and tissue engineering are possible alternatives to whole
organ transplantation. For the liver, transplantation of the most logical
source of cells, hepatocytes, is both laborious and inefficient. Recognizing
the successful paradigm of hematopoietic stem cell (HSC) transplantation,
there is renewed interest in the clinical utility of specific stem cells
for therapeutic application. We have developed three mouse models to
study the inherent regenerative capacity of the adult organism liver.
We are currently investigating the humoral contribution from bone marrow
to liver repair and regeneration. Ongoing studies address the responsible
cell type, mechanism of fusion and nuclear re-programming, inducibility
of the phenomenon, and overall relevance to liver function. In addition
we are examining the issue of tolerance to bone marrow derived hepatocytes
with reference to hepatocyte transplantation in both the syngeneic and
allogeneic host.
The concept of tissue committed stem cells is a fundamental premise of
biology and has served as the paradigm for the regeneration and renewal
of postnatal tissue. Unique among solid organs, the liver parenchyma
possesses significant regenerative potential after acute injury, able
to restore completely lost liver mass within days, without the activation
of a stem cell compartment. The oval cell is the liver-specific stem
cell; a blast-like cell capable of self renewal and multipotent differentiation,
the oval cell can only be identified in the setting of chronic liver
injury when resident hepatocytes are unable to enter the cell cycle to
restore liver mass. Wnts are a collection of secreted proteins that are
evolutionarily conserved, and have been shown to play diverse roles in
cell proliferation and differentiation during both development and postnatal
life. Similar to their role in tissue morphogenesis, Wnt proteins have
been recently determined to be major regulators of postnatal cell proliferation
and differentiation. We are currently studying the role of the Wnt-ß-catenin
signaling pathway in the regeneration of liver parenchyma in response
to both acute and chronic injury.
