Biomedical Engineering Reference
In-Depth Information
still the most important cellular resource in clinical situations, in which paren-
chymal liver functions need to be reconstituted.
Hepatocytes isolated from pig or human livers as well as immortalized human
hepatocytes have been tested in extracorporeal liver devices. Transplanted human
hepatocytes have been shown to engraft in the recipient liver and to respond to
growth stimuli in vivo [
28
-
30
]. Despite a high proliferative capacity of hepato-
cytes, which can undergo more than 69 cell doublings or a 7.3 9 10
20
-fold
expansion [
31
] in vivo, the proliferation capacity in cell culture is limited.
This lack of in vitro expansion protocols has stimulated the search for alter-
native cell sources, which can either expand in cell culture or can be easily
harvested from the body in large quantities. Immortalized hepatocytes derived
from adult and fetal tissue are restricted to ex vivo applications and have been
applied in extracorporal liver devices. Human fetal liver derived hepatoblasts have
been applied in a small number of patients with acute liver failure [
32
] and
recently in one patient with hereditary bilirubinemia [
33
]. These cells are also
being tested as a cellular substrate for bioartificial liver devices [
34
]. Although the
isolation of clinical grade stem/progenitor cells from human adult livers has been
described, clinical applications were not yet reported.
It has been proposed that (subpopulations of) adult hematopoietic stem cells (HSC),
mesenchymal stromal cells (MSC), and cord blood stem cells (CBSC) can transdif-
ferentiate into hepatocytes after transplantation, but the efficacy, by which these cells
spontaneously form hepatocytes and liver tissue in animal experiments, still seems
questionable [
35
-
39
]. As an alternative concept, HSC, MSC, and CBSC are being
applied in patients with chronic liver disease with the therapeutic aim to protect resident
hepatocytes from injury, induce liver regeneration, and to initiate tissue remodeling.
High therapeutic expectations have been attributed to embryonic stem (ES) cells
and, more recently, iPS cells. These cells can be maintained in a state of pluripotency
for long periods of time, grown in large quantities [
40
-
45
], and differentiated into
virtually all cell types of the body. ES-like cells have been generated by transfer and
simultaneous expression of four genes and termed induced pluripotent stem (iPS)
cells. The direct transcription factor-mediated conversion of fibroblasts into hepatic
cells, which could at least temporarily rescue a murine model of metabolic liver
failure, was recently demonstrated by two independent groups [
46
,
47
]. To date, it
remains speculative, whether direct ''trans-programming'' of adult stem cells or
fibroblasts into the desired phenotype by forced expression of sets of transcription
factors represents an alternative approach and may circumvent the state of pluri-
potency, which is associated with teratoma formation in transplanted recipients.
10.3.1 Modes of Therapeutic Activity
Various modes of therapeutic activity have been proposed for transplanted cells.
Transplanted primary hepatocytes, fetal hepatoblasts, and adult liver progenitor
cells engraft in the recipient liver and function as parenchymal liver cells. In vitro
