"Furthermore, we're talking about significant amounts of functional liver tissue -- up to 40 percent in one case we studied," said Dr. Neil Theise, first author of the cover report for HEPATOLOGY's July issue. HEPATOLOGY is the monthly peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD). "The whole notion of a bone-marrow cell traveling around, becoming anything it wanted, is the first time I've had an idea that I couldn't see the limits of."
The discovery has implications for organ transplants, artificial livers, gene therapy and more, explained Theise, who is an associate professor of pathology at New York University School of Medicine.
Only in the last year have scientists in the field agreed that some animals, such as mice, can transform bone marrow into new liver tissue. Whether humans have liver stem cells at all has been a decades-old debate.
"The liver is an incredibly regenerative organ using its own cells," said Theise. "So some people have argued why invoke stem cells? A couple of studies have looked for them in humans but the data have never been definitive until now."
Theise and his team, which also includes investigators at Yale University School of Medicine and at Memorial-Sloan Kettering Cancer Center, started with a deceptively simple approach: only male cells carry the Y chromosome.
The researchers first examined samples of liver tissue from two women who had received bone-marrow transplants from male donors. They prepared the tissues and then stained them with chromosome-specific dye (Y chromosomes fluoresced as light green dots, X chromosomes as red). Between 5 and 20 percent of the women's liver cells (hepatocytes) and bile-duct cells (cholangiocytes) exhibited green dots.
"Since females carry only X chromosomes in their genetic makeup, the cells with Y chromosomes could only have come from their male marrow donations," explained Theise.
Four other patients in the study were men whose liver transplants came from women. Yet their tissue samples too showed Y-positive hepatocytes and cholangiocytes. Thus the female livers regenerated tissue from male cells -- "most likely from bone marrow," said Theise, "given our findings with the female patients."
The pathologist added that the significance of stem-cell regeneration is threefold:
- A patient's stem cells could potentially provide his or her own liver-cell transplant, solving both organ shortages and rejection issues. "When we identify what the stem cells look like, we could extract some from a patient's blood, grow them in culture, and then reinject them," he said.
- Because the liver also performs complex reactions such as protein manufacture and chemical detoxification, bile-producing artificial livers need a living component to replace the damaged organ completely. "Liver cells, ironically, are hard to grow in culture. But stem cells should be much easier," he said, because they have not yet differentiated.
- Stem cells can be excellent targets for gene therapy, enabling doctors to transplant bone marrow to permanently correct inherited liver diseases. According to Theise, the technique has already been demonstrated in mice by scientists at StemCells California Inc., a research company based in Sunnyvale.
Theise's current cover report is his third for HEPATOLOGY in recent months. Work leading up to the discovery was highlighted in the journal's December and January issues.
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"Liver from Bone Marrow in Humans," HEPATOLGY Vol. 32, No. 1 (July 2000), by Neil Theise MD, Manjunath Nimmakayalu PhD, Rebecca Gardner, Peter B. Illei MD, Glyn Morgan MD, Lewis Teperman MD, Octavian Henegariu MD, Diane S. Krause MD PhD.
(Theise, Gardner, Morgan, Teperman: New York University School of Medicine; Nimmakayalu, Henegariu, Krause: Yale University School of Medicine; Illei: Memorial-Sloan Kettering Cancer Center)
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AASLD is the leading medical organization for advancing the science and practice of hepatology. Founded by physicians in 1950, AASLD's vision is to prevent and cure liver diseases. Today, AASLD provides representation and education for nearly 2,400 liver researchers, physicians, and surgeons worldwide. Visit AASLD's website at: http://www.aasld.org