Nov. 14, 2000 CHAPEL HILL - After studies spanning more than a decade, scientists at the University of North Carolina at Chapel Hill 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 list of patients awaiting liver transplantation is 15,700 nationally, but only 4000 liver transplants have been performed.
"Liver transplantation for end-stage liver disease is severely limited as a therapy for the vast majority of patients. Chronic end-stage liver disease accounts for approximately 50,000 deaths annually in the United States.
Since one donor organ helps only one or two recipients, there is an increasing gap between donors and transplant candidates over the past decade," said Lola Reid, PhD, professor of cell and molecular physiology at UNC-CH School of Medicine and the Program in Molecular Biology and Biotechnology.
In a report published in the Proceedings of the National Academy of Sciences, October 24, Reid and research associate Hiroshi Kubota, PhD, describe 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 explained.
"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 have long been 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 the paradox. 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.
"And the point is that 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. The young cells are the only ones capable of going through the whole lineage," Reid explained. 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, according to Reid, whole livers used for organ transplantation are exquisitely sensitive to a lack of oxygen, or ischemia, especially when at body temperature (warm ischemia). This means they must come from the 1% 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% of donors."
These are the "tissue donors" (including donors of heart valves, corneas, skin). The majority are young people under 40 years of age and result from accidents and gunshot wounds.
Reid adds: "Unlike older, polyploid cells, the liver stem cells and other diploid cell subpopulations can be cryopreserved, frozen and stockpiled. This facilitates the ability to fully screen and characterize the cells before using them in patients and enables the cells to be shipped worldwide."
In liver cell therapy, suspensions of liver cells would be injected into the liver or spleen of patients with liver failure and should reconstitute the patient's liver functions.
"Thus, each donated liver can be used to treat many patients, and the surgical procedures will be much safer and easier on the patient and much more economical than whole-organ transplantation," Reid said.
"We believe that if transplanted liver stem cells and other diploid cell subpopulations can expand and differentiate in a patient with liver disease as well as they do in culture or in animal model systems, they might provide a life-saving alternative to transplants. We are hoping to test this possibility next year in the first clinical trials."
Support for Reid's research comes from the National Institutes of Health.
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