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Science Translational Medicine  24 Jan 2018:
Vol. 10, Issue 425, eaar7522
DOI: 10.1126/scitranslmed.aar7522


An in vivo selection strategy identifies an antibody that induces stem cells to differentiate into microglia-like cells, migrate to the brain, and reduce β-amyloid plaques in mice.

The goal of regenerative medicine is to replace or repair damaged tissue to reestablish normal function. That requires getting the right cells to the right location. Toward that end, Han and colleagues devised a strategy to engineer hematopoietic stem cells to migrate and integrate into brain tissue to repair cellular damage that occurs in neurodegenerative illnesses, such as Alzheimer’s disease (AD).

Han et al. reasoned that they could identify antibodies that promote hematopoietic stem cells to differentiate and migrate into the brain. Using bone marrow stem cells, the investigators expressed 108 unique antibodies that were derived from a human single-chain fragment variable phage library. They designed the antibodies to be displayed on the plasma membrane, where they could bind to membrane-associated proteins on the cell surface. A pool of cells expressing the different antibodies was transferred to lethally irradiated mice; seven days later, brain tissue was sequenced to identify which antibody genes were present. After repeated testing, the investigators focused on one specific antibody gene sequence, called B1, that induced cells to migrate to the brain, where they expressed microglial cell markers and formed an extensive microglial-like network. Similarly, when human or mouse stem cells were treated with recombinant B1 antibody, they adopted a microglial morphology, expressed microglial markers, and behaved like microglia; they were robustly phagocytic and took up fluorescently labeled β-amyloid (Aβ) peptide. The investigators found that the B1 antibody binds vimentin, but exactly how that promotes differentiation and migration remains unclear. The migration of microglia-like cells to brains was induced by irradiation or pathologic Aβ plaque accumulation, suggesting that a signal generated by brain injury is important in their recruitment. Remarkably, these microglia-like cells were able to reduce pathologic Aβ plaque formation in a mouse model of AD.

Thus, a migration-based selection strategy provides a powerful approach to generate and identify rare cells that migrate, integrate into tissue, and modify disease pathogenesis. In addition, this antibody-based approach immediately yields a potential therapeutic in hand. These findings provide an interesting new therapeutic avenue for neurodegenerative, neuroinflammatory, and neuroinfectious illnesses. Moreover, a wide array of disease modifying therapies might be possible by selecting a desired cellular phenotype and tissue tropism.

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