Mature liver cells generated from bone marrow study in mice turns embryology on its head; implications are multifold

December 21, 1999

Alexandria, VA -- A new study shows that some mature liver cells in adult mice are generated from bone marrow cells, altering prevailing views on cell differentiation and stem cell potential.

Using radiation, researchers completely destroyed the bone marrow of female mice and replaced it with marrow from male mice. During a six-month follow-up period, they discovered that up to 2.2 percent of mature liver cells - called hepatocytes - in the female mice were derived from the donated bone marrow. Donor cells were identified by the presence of a Y chromosome, found only in males.

The study, by Neil D. Theise, M.D., New York University School of Medicine, Diane Krause, M.D., Ph.D., Yale University School of Medicine, and colleagues, is to be published in the January issue of HEPATOLOGY, the monthly peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).

The implications of the work are multifold. "It's been argued whether there is in fact a liver stem cell; this, in combination with previous studies, nails down that there is," said Theise. "If we can isolate these cells, we have targets for gene therapy and the possibility of stem cell transplantation, rather than whole-organ transplantation. There's also the possibility of expanding cells in culture and creating an artificial liver."

The discovery also turns embryology on its head. Textbooks teach that tissues in the developing embryo come from three specific cell layers - ectoderm, mesoderm and endoderm. Organs such as the liver are supposedly derived only from endoderm; bone marrow is derived from mesoderm.

"This paper, in association with others, shows that's not true," said Theise. "Bone marrow, derived from mesoderm, can become liver cells. The limits of cell differentiation are not bound by embryologic origin."

In addition, Theise and colleagues demonstrated that severe injury is not necessary for the formation of mature liver cells from bone marrow cells. A study published in May found that severe toxic injury to the liver provoked liver cell regeneration from bone marrow cells.

"Our work shows the possibility of low-level movement of stem cells from the bone marrow to the liver, all the time," said Theise. "The activity of these cells may not be simply a response to injury, which radically alters the way we look at liver regeneration."

The next step, he said, is to isolate the subset of cells that become mature liver cells. "We don't know if these cells are dedicated to becoming liver cells, or if they have multiple possible endpoints," said Theise. "We need to find the subset, or subsets, of cells that are capable of maturing into liver cells."

As for the implications and questions the research raises within the concepts of cell differentiation, "I think all bets are off - we have no rules to guide us," said Theise. "Every cell contains the whole genome, so maybe [changing a cell's behavior is simply a matter of] putting the cell in the right microenvironment. I no longer have logical reasons to draw a line anywhere."

Other research has shown that some mature skeletal muscle cells are derived from bone marrow stem cells; preliminary work by Theise and colleagues confirms this finding, and other work demonstrates that in response to lung injury, some mature lung cells also are formed from bone marrow cells.
AASLD is the leading medical organization for advancing the science and practice of hepatology. Founded by physicians in 1950, AASLD'd vision is to prevent and cure liver diseases. Today, AASLD provides representation and education for more than 2,200 liver researchers, physicians, and surgeons worldwide.

Researcher Contact: Dr. Neil Theise

Media Contact: Kirk Monroe

K-M Communications

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