Early reports that bone marrow stem cells could colonize the brain and differentiate into neurons raised hopes of an abundant and accessible supply of cells for brain repair. However, a different explanation has since been offered for these observations: instead of undergoing transdifferentiation to generate new neurons, the bone marrow-derived cells (BMDCs) fuse with pre-existing neurons. Previously, this fusion phenomenon was only seen in vitro, but two new reports confirm that it occurs in the living brain.
In one study, Alvarez-Dolado et al. used a Cre/loxP-based cell-marking technique to detect cell fusion. They used a mouse line called R26R, which carries a LacZ reporter gene that contains a 'stop' cassette flanked by loxP sequences. They irradiated the mice, then reconstituted their bone marrow with a BMDC line that expressed green fluorescent protein (GFP) and Cre recombinase. When BMDCs fused with R26R cells, the Cre recombinase excised the stop cassette between the loxP sites, thereby permitting LacZ expression.
The authors found LacZ-expressing cells in the liver and heart, and also in the Purkinje cell layer of the cerebellum. Each LacZ-expressing Purkinje cell contained two nuclei, only one of which had a typical Purkinje cell nuclear morphology. To see whether any transdifferention events had taken place, the authors also screened the recipient mouse tissues for non-haematopoietic cells that expressed GFP but not LacZ. No such cells were found.
In the other study, Weimann et al. transplanted GFP-expressing BMDCs from male mice into irradiated female mice, and they also detected binucleate Purkinje cells. Only one nucleus in each cell contained the Y chromosome, confirming that the two nuclei came from different mice. The binucleate state could be maintained for at least 1.5 years, and the donor nucleus eventually acquired the morphology of a Purkinje cell nucleus. Moreover, the donor nucleus seemed to activate Purkinje cell-specific genes, implying that it had become reprogrammed.
So, do these findings quash the idea of turning bone marrow stem cells into neurons? It certainly seems that BMDCs are unlikely to provide a significant source of new neurons, but perhaps cell fusion could be harnessed in other ways for therapeutic purposes. For example, Alvarez-Dolado et al. hint that it might provide a mechanism for repairing damaged cells, and this tantalizing possibility should provide the impetus for further investigations.
ORIGINAL RESEARCH PAPERS
Alvarez-Dolado, M. et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425, 968–972 (2003)
Weimann, J. M. et al. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nature Cell Biol. 5, 959–966 (2003)
About this article
Cite this article
Wood, H. State of the union. Nat Rev Neurosci 4, 938 (2003). https://doi.org/10.1038/nrn1283