Failure of Bone Marrow Cells to Transdifferentiate into Neural Cells in Vivo

Abstract

Reports have suggested that adult mouse bone marrow cells (BMCs) are capable of transdifferentiating into cells with neural characteristics in the central nervous system (CNS) (1, 2). Because side-population (SP) cells within whole bone marrow are hematopoietic stem cells that can reconstitute the BMC population and are capable of differentiating into other types of cells such as cardiac myocytes and endothelial cells (3-5), wecells. Their close association with blood vessels and the lack of morphological features of neural cells suggested that they were hematopoietic. The brains from Rosa26 control mice had robust P-Gal staining in neural as well as blood cells.Because injury increases SP transdifferentiation in other tissue systems (5), we tested whether neural injury would cause donor cells to transdifferentiate into neural-like cells. Four Table 1. Summary of experimental manipulations and results. ND, not done. Type and number of mice receiving injury to the Brains with Type of cells brain donor-derived transplanted neural cells/brains Contusion injury Stab injury No injury analyzed SP cells 2 4 2 0/8* BMCs ND 7 5 0/12* *50 to 100 coronal sections containing more than 106 neural cells were analyzed per brain.surmised that they too would transdifferentiate into neural cells.To test this, 8 C57B1/6 (B6) mice were treated with a lethal dose of irradiation and transplanted with 2 X 103 SP cells derived from the Rosa26 mouse. The Rosa26 mouse carries the LacZ gene that is constitutively expressed in most cells including neural and SP cells and is an unambiguous marker for donor-derived cells (6). Ten to 12 weeks after transplantation, 80 to 95% of the recipient blood cells were LacZ positive. Four months after transplantation, the CNS of two of the recipient mice were inspected for cells derived from the Rosa26 donor with standard X-gal cytohistochemistry. In coronal sections (50 to 100 sections per brain representing more than 106 cells per brain) taken throughout the full extent of the brain, including the olfactory bulbs and cervical spinal cord, the only P-galactosidase (P-Gal)-positive cells detected were a few cells (<5) that were associated with blood vessels. These P-Gal-positive cells had a globular morphology and no processes that would suggest that they were neural mice with SP transplants underwent cortical stab injury, and two underwent cortical contusion injury (7) 4 months after the transplant. Reconstitution of the hematopoietic system is considered stable and complete around 4 months after BMC or SP transplantation. Therefore, cells capable of transdifferentiation should be in place at that time. One month after cortical stab injury and 4 months after contusion injury, no 3-Gal-positive cells were observed in brains (fig. S1) or cervical spinal cords except a rare few associated with blood vessels. We concluded that adult bone marrow SP cells or cells derived from them were incapable of transdifferentiating into neural cells in this experimental system.Because SP cells will reconstitute the BMC p...

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