Biomedical Engineering Reference
In-Depth Information
support systems and cell therapies are currently limited by the availability of good
quality hepatocytes. A renewable source of highly metabolically competent
hepatocytes will be essential for any successful bioartificial liver system. To date
porcine hepatocytes are most commonly being used with limited acceptance due to
ongoing concerns of xenozoonosis. Immortalized human hepatocytes have not
shown expression of prerequisite hepatocyte function including ammonia detoxi-
fication. Other limitations of first-generation bioartificial liver systems, which need
to be solved, include excess device complexity, insufficient number of hepatocytes
to support a failing liver, early hepatocyte death, and absence or loss of differ-
entiated function.
The application of stem cells in liver cell therapies seems to be a promising
approach for the treatment of liver diseases. However, several issues still have to
be addressed to fulfil this promise. We need to identify, both inside and outside of
the liver, the stem cell candidates that are able to form mature hepatocytes in vitro
and functional liver tissue after transplantation in vivo. The fundamental molecular
pathways involved in the differentiation of hepatocytes and cholangiocytes from
stem/progenitor cells, the factors that are responsible for in vitro differentiation of
various stem cells into hepatocytes, the mechanisms involved in the fusion of stem
cells and hepatocytes and the aspects that can potentially enhance these mecha-
nisms need to be studied in more detail. With future progress in stem cell research,
the various stem cell sources including hepatic stem/progenitor cells, embryonic,
and adult extrahepatic stem cells should provide great opportunities for the
treatment of liver disorders.
Additional work is also needed in the development of an ideal gene delivery
system. The efficacy of delivery and the level of transgene expression achieved by
the current methods have resulted in phenotypic correction of various hereditary
liver diseases in animal models. The most efficient vehicles for gene delivery to the
liver developed so far are viral vectors. Among the viral vectors applicable to liver
gene delivery, lentiviral vectors appear to have great advantage because of their
ability to transduce the liver cells at resting state and generate persistent gene
expression. Gene toxicity by insertional mutagenesis with the transactivation of
potentially harmful genes and interactions of the host immune system with the
viral proteins and the therapeutic product need to be studied in more detail. Active
participation of hepatologists in gene therapy research will accelerate the process
in turning gene therapy into a common practice for the treatment of various
diseases through the liver.
In summary, advanced approaches in regenerative hepatology will cover
strategies to improve endogenous liver regeneration, to correct monogenetic liver
diseases by gene therapy, and to support organ function with additional hepatic
cells, either in extracorporal devices or as cell transplants. For the latter aspect,
improved cell isolation and propagation techniques to utilize cells from donor
organs or advanced stem cell-differentiation protocols become of utmost impor-
tance to ensure the supply of functional hepatic cells.
