LONDON - It may be possible one day to encourage stem cells from the bone marrow to grow into almost any cell type in the body, scientists believe. A recent study has proved that bone marrow stem cells can differentiate into mature liver cells in humans.

Malcolm Alison, reader in pathology at Imperial College School of Science, Medicine and Technology at Hammersmith Hospital in London, told BioWorld International: "If it is possible for bone marrow cells to turn into liver cells, I think that under the appropriate environments we could encourage bone marrow stem cells to differentiate into almost any cell type in the body. This would make it possible to grow cells to replenish the major organs of the body associated with human morbidity and mortality, allowing new treatments for conditions such as renal failure and myocardial infarction."

The approach would overcome the ethical problems associated with using embryonic stem cells, Alison added. It also may be possible to correct certain genetic disorders by genetically modifying bone marrow stem cells and returning them to the affected organ, he said. "For example, it may be possible to treat clotting disorders, such as Factor IX deficiency, by inserting a good gene into these cells and then encouraging them to differentiate into liver cells. Clinicians believe that you only need to colonize the liver with 2 percent of cells bearing a working gene for Factor IX to correct this deficiency."

Nick Wright, head of the Histopathology Unit at the Imperial Cancer Research Fund in London, said it may be possible to stimulate liver regeneration using cells from a patient's own bone marrow. "This would be particularly useful for patients whose livers have been damaged due to drug side effects, or through surgery to remove cancers that have spread to the liver, and where there is insufficient functioning liver remaining," he said.

The work is reported in the July 20, 2000, Nature in an article titled "Hepatocytes from non-hepatic adult stem cells." The group, funded by the Imperial Cancer Research Fund, one of the UK's largest cancer charities, is looking for partners to help develop the findings.

Alison has worked on liver stem cells for many years and discovered several years ago that the cells that line the biliary tract also could act as stem cells for the liver, and differentiate into hepatocytes. "Scientists have believed until recently that each organ had its own population of stem cells, which could differentiate into a limited range of cell types appropriate to that organ," he said. "So, for example, in the bone marrow there is thought to be a multipotential stem cell which can divide into a family of descendents such as white blood cells, red blood cells and so on."

Recent findings have proved, however, that there is more plasticity in the system than had been thought. "Studies in mice," Alison said, "have shown that blood stem cells can turn into voluntary muscle cells, and a year ago other researchers showed that bone marrow cells in mice could turn into hepatocytes. What we have now done is to prove that the same thing can occur in humans."

Alison and his colleagues did this by studying patients who had received bone marrow transplants, following systemic chemotherapy for cancer. So that they could tell cells derived from the donor from those of the recipient, they looked only at female patients who had received bone marrow from a male donor.

Researchers discovered that between 2 percent and 3 percent of the hepatocytes in the patients' livers were of male origin, and must therefore must have differentiated from stem cells present in the donor marrow. Further tests proved that these cells were functioning liver cells, and not inflammatory cells that had invaded the recipients' livers.

The percentage of cells of donor origin is probably more like 4 percent to 6 percent, Alison added, because liver cells are large cells and so not every cell which is of male origin in every section will have contained the target sequence of the Y chromosome that was recognized by the probe.

Alison said, "It seems likely that these cells only colonized these patients' livers because these organs were already damaged by the graft-vs.-host disease that frequently follows a transplant."

The finding is highly significant because it does away with the need to pursue strategies using embryonic stem cells or cells of animal origin, which are fraught with ethical problems and, in the case of xenotransplantation, the risk of transmitting hitherto unidentified viruses. "In addition," Alison said, "it avoids the problem of graft rejection and possibly long term immunosuppression that follow use of donor organs or cells." An added advantage is that certain drugs will forcibly eject stem cells from the bone marrow, making it easy to harvest them from the patient's peripheral blood.

Future studies by Alison and his colleagues will include looking for stem cells of donor origin in other organs such as the kidney. Using postmortem tissue, they also will see if these cells have differentiated into brain cells.

The group plans to collaborate with other researchers working on hepatitis C. Alison said, "We would like to encourage blood stem cells to turn into liver cells and genetically modify them, probably by infecting them with a retrovirus which transcribes a gene encoding interferon, which is an antiviral cytokine. Putting these cells into the livers of people infected with hepatitis C could provide a potential antiviral therapy, since it is well known that chronic carriers can develop cirrhosis and/or liver cancer."

The team also wants to investigate the use of autologous cell transplantation as an alternative to liver transplants, particularly given the extreme shortage of donor organs.

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