January 2001 Vol
2 No 1
Nature Reviews Neuroscience 2, 8 (2001)
Recent advances in cloning and embryonic stem cell technology have raised hopes that tissue for transplantation may be grown in vitro from a single somatic cell taken from the recipient. This would solve the problems of organ shortage and transplant rejection in one fell swoop. However, in reality, embryo cloning is extremely inefficient, not to mention controversial, and human stem cell lines have proved more difficult to establish and maintain than their mouse counterparts. Therefore, it might be argued that time would be better spent looking for alternative, more accessible, sources of pluripotent stem cells. It is becoming increasingly clear that lineage-specific stem cells, and even fully differentiated cells, show remarkable capacities for switching fate. Now, Science reports on two independent studies showing that bone-marrow-derived cells can colonize the brain and differentiate into neurons.
Brazelton et al. used adult bone marrow cells expressing green fluorescent protein (GFP) to rescue lethally irradiated adult mice. By cell sorting, they found that up to 20% of GFP-positive cells in the brain lacked expression of haematopoietic markers. However, this did not prove that they were neurons, as bone marrow cells can also generate microglia. To overcome this problem, the researchers used laser scanning confocal microscopy to look for expression of GFP and neuronal markers together in olfactory bulb (OB) sections. 8–12 weeks after transplantation, 0.2–0.3% of the total OB neuronal population was GFP-positive. Most of these cells were found in the superficial axon and glomerular layers, and most resembled neuroblasts rather than mature neurons. Overall, this work shows that a dramatic change in cell fate occurs in marrow-derived cells located in the CNS.
Mezey et al. used mice mutant for the PU.1 gene, which are unable to produce cells of the lymphoid and myeloid lineages. These mice die unless they receive a bone marrow transplant within 48 hours of birth. Female mutant mice received an intraperitoneal injection of bone marrow from an adult wild-type male donor during the first postnatal day. Their brains were examined at 1–4 months of age to look for expression of the neuronal marker NeuN, combined with the presence of the Y chromosome. They found that 0.3–2.3% of NeuN-positive cells were of male origin. The double-labelled cells were found predominantly, but not exclusively, in the cerebral cortex.
Bone marrow cells have already been shown to have neurogenic potential in vitro, but these new findings are important because they show that these cells can also differentiate into neurons in vivo. However, predictions about possible therapeutic applications are probably premature. For instance, the recipient mice used in these studies were either newborn, or had received doses of radiation that could mildly injure the brain tissue, perhaps creating a more permissive environment for neuronal differentiation. To take full advantage of the possibilities presented by these experiments, it might be necessary to develop techniques for isolating the subset of cells that show neurogenic potential, or to identify growth factors that encourage bone marrow cells to differentiate as neurons. What we can conclude is that these data lend a new meaning to the phrase 'crossing the blood–brain barrier'!
ORIGINAL RESEARCH PAPERS
Brazelton, T. R.
et al. From marrow to brain: expression of neuronal phenotypes in adult
mice. Science 290, 1775–1779 (2000) PubMed
Mezey, E. et al. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290, 1779–1782 (2000) PubMed