Brain cell origin solved

New findings lay to rest a debate over the origin and cell lineage of macrophages found in mouse brains -- they come from progenitor cells in the embryonic yolk sac and are self-renewing, and are not derived from bone marrow precursors like other macrophages in the body.

A mouse macrophage
Image: Wikimedia commons, Obli

The results, published online today (21 October) in Science Express, may also hold implications for the treatment of neurodegenerative diseases."It has been quite controversial where [microglia] come from in embryonic life," said neurologist linkurl:Richard Ransohoff;http://my.clevelandclinic.org/staff_directory/staff_display.aspx?doctorid=814 of the Cleveland Clinic, who was not involved in the research. This study "showed unequivocally that microglia come from these yolk sac progenitors."Microglia are macrophages that reside in the central nervous system. They are important for maintaining healthy brain function and have been associated with many neurodegenerative and brain inflammatory diseases, but where they come from -- both initially and throughout life -- has been a bit of mystery. Some mice studies suggested that they could be replaced by bone marrow progenitor cells, but a couple of papers linkurl:published in Nature Neuroscience;http://www.nature.com/neuro/journal/v10/n12/index.html in 2007 suggested that these experiments, which involved irradiating the animals, introduced artifacts and were "completely un-physiological," Ransohoff explained. Whether or not the bone marrow could contribute to the microglia in the brain under normal conditions has remained unclear, as has where the microglia cells came from initially.To answer these questions, immunologist linkurl:Miriam Merad;http://www.mountsinai.org/profiles/miriam-merad of the Mount Sinai School of Medicine in New York and her colleagues created mice with green fluorescent protein (GFP) attached to the fractalkine receptor (CX3CR1), which is found on early myeloid progenitors and microglia. Monitoring the mice, they saw evidence of microglia when the embryos were around 10.5 days old, and the phenotype of the cells suggested they were derived from the yolk sac.To confirm this, the researchers labeled the yolk sac cells with yellow fluorescent protein (YFP) at various times throughout development, and watched where they went. They found that some myeloid progenitor cells in the yolk sac indeed became microglia, and the cells that give rise to microglia are produced in a very limited time window, around days 7 to 8 of embryonic development. Furthermore, only a few percent of circulating and non-brain tissue macrophages carried the YFP label, suggesting they were derived from another source. "The paper is highly influential," developmental neuroscientist linkurl:Payam Rezaie;http://www.open.ac.uk/science/lifesciences/people/people-profile.php?staff_id=Payam%26%26Rezaie of The Open University in the UK, who did not participate in the research, told The Scientist in an email. The authors went on to show that bone marrow progenitor cells do not contribute to the microglia in the healthy adult brains, in contrast to when the mice are irradiated. This supports the notion that resident microglia (i.e. the embryo-derived cell population) are maintained independently through self-renewal."In a normal healthy animal, the majority of cells that appear to populate the adult brain are derived from the yolk sac in the embryo...and they persist for a long time," said neuroimmunologist linkurl:Hugh Perry;http://www.southampton.ac.uk/biosci/about/staff/vhp.page of the University of Southampton, who was not involved in the study. What this means for the function of these cells is unclear, however, he added. After irradiation, for example, bone-marrow derived cells that look like microglia do end up in the brain, meaning that "macrophage cells have the capacity to enter the brain and adopt the morphology of microglia" under some conditions, Perry said. The results could have therapeutic implications for neurological diseases, said Ransohoff. "Your strategy for dealing with the bad consequences of microglial or macrophage activation in neurological disease are going to depend on where you think they came from," he said. If the cells are coming from the bone marrow, a logical solution would be to block them from getting to the brain in the first place, he explained. On the other hand, if the resident microglia are the problem, they are already in the brain, so "you have to come up with compounds that directly address microglial activation," he said. "Those are two totally different therapeutic strategies."Additionally, this research emphasizes the importance of embryonic work, study author Merad told The Scientist. "Our work reveals that there are processes that only occur during early embryonic life," she said. "That shows that we need to work on embryos if we want to understand all the molecular program to make these cells..[and] the biology of these brain diseases."F. Ginhoux, et al., "Fate mapping analysis reveals that adult microgliaderive from primitive macrophages," linkurl:SciencExpress,;http://www.sciencexpress.org 10.1126/science.1194637, 2010.
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