Study Raises Doubts About Ability of Bone Marrow-Derived Adult Stem Cells to Differentiate

October 13, 2003
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A study led by UCSF investigators indicates that bone marrow-derived cells from mice that are transplanted into other mice fuse with cells in the animals' heart, brain and liver, and take on their characteristics. The finding is significant in part because it offers strong, new evidence that bone marrow-derived cells do not actually differentiate into specialized cells themselves, a goal of some cell-transplant therapy.

The findings, reported in the advance, on-line issue of Nature on Oct. 12, contrast with previous studies that have suggested adult stem cells derived from the bone marrow -- a spongy tissue inside bones that makes blood cells -- were capable of specializing not just into blood cells, but into cells of the brain, heart and other tissues. These studies have raised hopes that cells that are progenitors of blood could be used to replace damaged tissue in critical organs.

The new findings provide the first indication that cell fusion, rather than differentiation, occurs when bone marrow-derived cells migrate to the heart and the brain of mice. They also support previous studies showing fusion of blood cells in liver, and in cell culture.

Given this evidence, the researchers say, clinical trials to study whether implanted bone marrow-derived cells could be used to replenish damaged cells in patients with diseases of the heart, brain and liver should be postponed until more research has been conducted.

"Our study raises serious questions about whether bone marrow-derived cells are capable of trans-differentiation," says the senior author of the study, Arturo Alvarez-Buylla, Ph.D., professor of neurosurgery at University of California, San Francisco (UCSF).

"The finding raises major questions about the plasticity of adult blood stem cells," concurs co-author Sean J. Morrison, Ph.D., a Howard Hughes Medical Institute assistant investigator and assistant professor of internal medicine and of cell and development biology at University of Michigan.

At the same time, cell fusion, itself, should be explored further, the researchers write in their paper, suggesting that it might contribute to development and maintenance of some cell types, and could be one of the body's strategies for repairing damaged cells. "My hunch is that fusion might be a physiological mechanism that the body has devised to import DNA from blood cells into damaged cells in various tissues," says Alvarez-Buylla.

If fusion does play a role in repair of cells in the body, or even if it doesn't, the new findings suggest that it might be possible to harness the technique therapeutically, he says.

Earlier this year, researchers reported that bone marrow-derived cells fused with damaged liver cells in experimental mice and helped to improve their damaged livers.

In the current study, led by Manuel Alvarez-Dolado, Ph.D., a postdoctoral fellow in the Alvarez-Buylla lab, in collaboration with the Morrison laboratory, bone marrow cells from one set of mice were grafted into the bone marrow of another set of mice whose own marrow had been irradiated. The cells of both animal models had been genetically engineered to enable the scientists to detect if cell fusion occurred. Later, at one of two time points -- two months or four months -- the mice were sacrificed and their tissue examined.

The researchers determined that the cells, after circulating through the blood and migrating into different organs, fused with Purkinje neurons in the brain, cardiomyocytes (heart muscle cells) in the heart and hepatocytes in the liver, assuming their structural characteristics. The scientists detected no evidence of trans-differentiation without cell fusion. They did not detect cell fusion in skeletal muscle, gut, kidney or lung in their experiments, though it is possible, they say, that under different experimental conditions fusion might occur in these tissues.

Notably, the fused cells contained two nuclei -- one nucleus (which encases the body's genes) from the original cell and one from the blood cell. As such, they contained two sets of genetic instructions. The work raises the interesting question of how genes are controlled between the two nuclei and whether the genetic information derived from the blood contributes to the function of the host cell, says Alvarez-Buylla.

The current study provides hints, he says, that some of the genes from the bone marrow-derived cells might be down regulated, or inactive, which could explain the fused cells' healthy appearance. Whether cell fusion can help rescue damaged cells remains to be seen, he says. In any event, he says, the discovery that cell fusion occurs, at least in an animal model, "opens up some very interesting questions about how one cell dominates over another to maintain a functional hybrid."

"The fact that adult bone marrow-derived cells fused with pre-existing local cells, rather than trans-differentiating into new cells, under the experimental conditions that we used, means that they may do the same in the human body," says Morrison. "Therefore, clinical trials that are based on the idea that bone marrow cells can generate new cells in tissues like the heart should be re-evaluated. We urgently need a better understanding of the functional effects of cell fusion, the circumstances under which it occurs, and what cells are capable of fusing."

Other co-authors of the study were Ricardo Pardal, Ph.D., an HHMI postdoctoral fellow, and Hyun O. Lee, an undergraduate research assistant, both of the Morrison lab at University of Michigan; Dr. Carlos Lois, Ph.D., of the Picower Center for Learning and Memory at Massachusetts Institute of Technology; Jose M. Garcia-Verdugo, Ph.D., Department of Cellular Biology, University of Valencia, Valencia, Spain; and Klaus Pfeffer, Ph.D., of University of Dusseldorf.

The study was funded by grants from the National Institutes of Health, the Sandler Foundation, the Spanish Ministry of Science and Technology (Ataxias Cerebelosa), and the Deutsche Forschungsgemeinschaft (DFG). Ricardo Pardal was the recipient of a postdoctoral fellowship from the Spanish Ministry of Science and Technology.

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