May 1 2004. Just when many stem cell researchers had given up the ghost on the potential for adult stem cells to transdifferentiate into cells of other lineages, along comes new data to rekindle the debate. Reporting in tomorrow’s Lancet, Edward Scott and colleagues of the Program in Stem Cell Biology and Regenerative Medicine, University of Florida, Gainesville, have taken a retrospective, postmortem look at three women who had received hematopoietic transplants from male donors. Their findings, that male neural cells are present in the hippocampus of all three women, up to six years after transplantation, suggest that cells of the blood lineage can indeed give rise to cells of other lineages.
Hope that transdifferentiation would allow scientists to generate different tissue types from adult stem cells—and thus solve technical problems of tissue compatibility and ethical concerns about using embryonic stem cells—peaked a few years ago (e.g. see Mezey et al 2000). These hopes were then dashed when researchers reported that supposed transdifferentiated cells were actually chimeras that resulted from fusion of host and donor cells (see related news item ). In today’s Lancet paper however, first author Christopher Cogle and colleagues seem to rule out fusion as an explanation for male neurons in female brains. Using fluorescence in situ hybridization, Cogle tested brain samples from the three women for cells harboring X or Y chromosomes. This karyotyping showed that XY microglia were present in all samples. Though the authors failed to detect XY neurons or astrocytes in two of the women, who had died shortly after receiving peripheral blood stem cell transplants, they did find these cells in samples taken from the third woman, who had lived for 6 years after a bone marrow transplant.
Significantly, the authors failed to detect any XXY or XXXY cells. In addition, none of the women had had a male child, thus ruling out the possibility that XY neural stem cells from a fetus had once made their way into the brain tissue of the mother, a phenomenon known as post-partum microchimerism. Importantly, in the patient that had received the bone marrow transplant about 1% of neurons and astrocytes were male, a considerable amount. The authors suggest that previous CNS damage, caused by radiation and high-dose chemotherapy, may have created fertile ground for a bone marrow cell to transdifferentiate. It is also significant that most of the XY neurons were found in the subgranular layer of the dentate gyrus, one of only two sites in mammalian brains where neurogenesis is known to take place in adults.
According to the authors, these results suggest “that a transplantable haemopoietic cell responds to instructive neurotrophic cues, crosses the blood-brain barrier, migrates into CNS parenchyma, and activates neural-specific genetic programming.” In other words, the authors say, bone marrow can make brain. However, more experiments may be needed to convince many stem cell researchers. "The data may indicate that cells capable of providing neural cell differentiation were present in the grafts, but do not directly demonstrate that those were the same cells that provided hematopoietic engraftment," said David Scadden director of the Center for Regenerative Medicine and Technology at Massachusetts General Hospital, and codirector of the recently announced Harvard Stem Cell Institute. It will be interesting to see where the stem cell transdifferentiation debate goes from here (see related live discussion).—Tom Fagan.
Cogle CR, Yachnis AT, Laywell ED, Zander DS, Wingard JR, Steindler DA, Scott EW. Bone marrow transdifferentiation in brain after transplantation: a retrospective study. Lancet May 1 2004;363:1432-1437. Abstract