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After studies spanning more than a decade, scientists at the University have
become the first to identify and purify hepatic stem cells, progenitor cells
capable of regenerating liver and bile duct tissue.
The accomplishment marks a milestone for future liver regeneration through
cellular therapy, a treatment that could drastically reduce the need for
whole-organ transplant in people with a variety of liver diseases. The current
number of patients awaiting liver transplantation is 15,700 nationally, but
only 4,000 liver transplants have been performed.
"Liver transplantation for end-stage liver disease is severely limited as a
therapy for the vast majority of patients," said Lola Reid, professor of cell
and molecular physiology at the School of Medicine and its Program in Molecular
Biology and Biotechnology.
"Chronic end-stage liver disease accounts for approximately 50,000 deaths
annually in the United States," she said. "Since one donor organ helps only one
or two recipients, there is an increasing gap between donors and transplant
candidates over the past decade."
In a report recently published in the Proceedings of the National Academy of
Sciences, Reid and research associate Hiroshi Kubota described another
first: the colonization in lab dishes of a multitude of rat hepatic stem cells
from a single cell. "We are the first to develop culture conditions that permit
one to put into culture these cells at densities of a single cell in the dish
and then have it grow into a colony," Reid said.
"People have been putting mature liver cells in culture for decades, but they
always had to put them in at very high densities or they didn't survive. This
meant you could never ask whether a given cell was capable of extensive growth
or capable of producing daughter cells of more than one fate. We now have
conditions in which a single cell can be put in and it will survive and grow
extensively."
Liver cells are renowned for their regenerative capacity in vivo, but in
culture they were found to go through only one or two divisions. No one could
explain why. This was exacerbated by the dogma in the field that all liver
cells are co-equal in their ability to grow and restore liver tissue. Reid and
her associates have shown that only the cells early in the lineage are capable
of repeatedly going through complete cell division.
"We have shown in this particular report that there's a maturational lineage of
liver cells, and that the cells at different stages of the lineages have
different capacities to grow," she said. "The liver stem cells, other
progenitors and young adult cells have two sets of chromosomes; that is, they
are diploid and go through complete cell division. Mature liver cells go
through DNA synthesis, but do not complete cell division resulting in increased
multiple sets of the chromosomes; that is, they are polyploid. Thus, the
younger cells go through complete cell division while in the older cells
division is incomplete.
"So if we want to restore a liver that's damaged, we have to get the young
cells because they are going to mature into the older cells," Reid added. "The
young cells are the only ones capable of going through the whole lineage.
"Thus, as we age, we shift more and more into those older cells, with the net
effect being a decline in the regenerative capacity of the liver.
In addition, whole livers used for organ transplantation are exquisitely
sensitive to a lack of oxygen, or ischemia, especially at body temperature
(warm ischemia), he said. This means they must come from the one percent of
donors who have undergone brain death but not heart arrest.
"By contrast, liver stem cells and the other diploid liver cell subpopulations
are more tolerant than the polyploid liver cells to warm ischemia, such that
they can be isolated from non-heart-beating donors, comprising the other 99
percent of donors," she said.
These are the "tissue donors," including donors of heart valves, corneas and
skin. Reid's research is funded by Renaissance (Incara) and by the National
Institutes of Health.
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