Fusion and confusion

LONDON — The ability of adult stem cells to differentiate and proliferate into different cell types has been questioned by research published last week indicating that they might simply fuse with existing cells, creating genetically mixed, tetraploid cells. A group working at the University of Edinburgh tracked the fate of fluorescent markers in mouse brain cells that were co-cultured with embryonic stem cells. Initial examination indicated that the adult brain cells had reverted to the less specialized status of the undifferentiated stem cells around them. However, the new cells were found to carry a transgenic marker and chromosomes derived from the embryonic stem cells. Genetic analysis confirmed that these new cells actually resulted from the merging of two cell types, so that they had twice the usual number of chromosomes. This suggested that rather than developing into new cell types, the cells were a genetic mix of the two cell types being cultured together ( Nature 2002, DOI: 10.1038/nature729). Professor Austin Smith, Director of the Centre for Genome Research at the University of Edinburgh and one of the authors of the study, commented: "The results indicated that the altered phenotype did not arise by direct conversion of brain to embryonic stem cells but rather through spontaneous generation of hybrid cells. The tetraploid hybrids exhibited full pluripotent character, including multilineage contribution to chimaeras. We propose that transdetermination consequent to cell fusion could underlie many observations otherwise attributed to an intrinsic plasticity of tissue stem cells." The second study, from a group at the University of Florida, Gainesville, showed that mouse bone marrow cells could fuse spontaneously with embryonic stem cells in culture. ( Nature 2002, DOI: 10.1038/nature730) It initially appeared that the bone marrow cells had transformed into stem cells, exhibiting the same surface characteristics. But, closer analysis showed that some of the bone marrow cells had fused with stem cells to produce cells with two or three times the normal complement of genetic material. Lead researcher Naohiro Terada, commented: "Spontaneously fused bone marrow cells can subsequently adopt the phenotype of the recipient cells, which, without detailed genetic analysis might be interpreted as dedifferentiation or transdifferentiation." The findings raise some doubt about the clinical value of using adult stem cells to produce other cell types, such as brain cells, to be used to repair damaged or diseased tissues. Smith commented: "The studies suggest a need for caution with regard to the therapeutic use of adult tissue stem cells. If they only make other tissues by fusing with existing cells rather than producing new cells, their utility for tissue repair and regenerative medicine will be greatly restricted." Several previous studies had shown that adult stem cells could develop into muscle, liver, brain and heart cells. It was thought that the adult cells reverted to a state similar to that of embryonic stem cells, which are even less specialized, before developing into the new cell types. This was surprising, as it had previously been thought that adult cells were committed to developing into only one class of cell. The latest studies suggest that the new cell types might have been produced by fusion between adult stem cells and other cell types rather than by differentiation. Terada said: "A potential problem is that reports discussing transdifferentiation of transplanted bone marrow cells into unexpected lineages such as hepatocytes and neurons in vivo tend to conclude donor origin of trandifferentiated cells on the basis of the existence of donor-specific genes such as Y-chromosome markers." He added: "We are not saying that this is wrong. But researchers should not conclude that their cells have changed developmental paths without checking if fusion is the cause." Smith considers that the findings made by his group underline the need for continued research with embryonic stem cells, which can differentiate into a variety of different cell types. "Our study indicates that calls for a halt to embryonic stem cell research are not scientifically justified and confirms the far-sightedness of the UK legislation." His group was recently granted one of the first licenses to carry out research with embryonic stem cells after approval was given by the House of Lords Select Committee on Stem Cell Research to extend research uses of human embryos to allow embryonic stem cell research. The new studies are likely to be considered when the US Senate is expected to discuss the issue in the next few weeks of whether to ban the use of cloning to create human embryos to be used in medical research. David Prentice, a biologist working at Indiana State University who is advising members of Congress who want to ban cloning of human embryo cells, was sceptical about the latest findings, considering that most studies still support the concept of plasticity in adult stem cells. But, Smith concluded: "While there is justifiably a great deal of interest in the broader applicability of adult stem cells, our findings illustrate that we are currently still very ignorant of their biology."

Fusion and confusion

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