PHILADELPHIA – Scientists at the University of Pennsylvania School of Veterinary Medicine have found a new wrinkle in the developmental biology dogma that cell differentiation occurs irreversibly as stem cells give rise to increasingly specialized types of offspring cells. The researchers have shown that certain mouse cells retain an ability to oscillate between very distinct blood cell types – B-cells and macrophages – long after what has been commonly regarded as the point of no return.

These latest findings on the phenomenon sometimes referred to as "lineage promiscuity" appear on the Web site of the journal Blood and will be published in the journal's print edition in March 2003.

"This work reveals that seemingly committed cells have more plasticity than we had thought," said senior author Andrei Thomas-Tikhonenko, assistant professor of pathobiology at Penn. "It appears there is at least a small window where terminally differentiated cells vacillate on which identity to adopt. We suspect that this phenomenon is not limited to B-cells and macrophages in mice."

Pushing mature cells into other lineages may offer a new way to replace cells involved in blood diseases and neurodegenerative disorders such as Alzheimer's disease. Scientists also say this approach offers the potential for converting lymphoma cells that are resistant to treatment into more manageable forms of cancer.

"We found that just two genes, EBF and Pax5, are turned off when B-cells are concerted into macrophages; Pax5 is a known oncogene implicated in the growth of B-cell lymphomas," Thomas-Tikhonenko said. "It's possible that by targeting this gene with drugs, we may be able to convert malignant B-cell lymphomas into much less harmful histiocytomas, tumors composed of relatively inactive macrophages."

Previous research has demonstrated that when B-cells are transplanted from an animal into a petri dish, the cells sometimes change into macrophages. Thomas-Tikhonenko and colleagues found that when the cells are returned to the animal, they generate spherical B-cell lymphomas, indicating that they have changed their identity yet again. Moreover, the cells could continue oscillating between B-cells and macrophages indefinitely, as many times as they were relocated.

"In other words, ‘unfaithful' cells that have strayed from their original identity can ‘come to their senses' and return to the original lineage," Thomas-Tikhonenko said.

Like all blood cells, B-cells and macrophages descend from hematopoeitic stem cells; however, as members of different families, the two cells do not share a common parent. B-cells arise from a lymphoid progenitor, while macrophages come from a myeloid progenitor.

"Until recently, it was believed that the various cell types of the blood are generated from stem cells in a controlled but irreversible fashion," said James Hagman, an immunology researcher at the National Jewish Medical and Research Center in Denver who was not involved in this research. "Now, Dr. Thomas-Tikhonenko and colleagues provide a new example of developmental flexibility. Together with other published results, these observations blur the concept of fixed cell types and provide new insights concerning potential uses for adult stem cells."

Thomas-Tikhonenko was joined in the research by Duonan Yu and Michael H. Goldschmidt of Penn's Department of Pathobiology, David Allman and John G. Monroe of Penn's Department of Pathology and Laboratory Medicine and Michael L. Atchison of Penn's Department of Animal Biology. The work was funded by the National Cancer Institute.