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Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment

Abstract

Gene therapy in the central nervous system (CNS) is hindered by the presence of the blood–brain barrier, which restricts access of serum constituents and peripheral cells to the brain parenchyma. Expression of exogenously administered genes in the CNS has been achieved in vivo using highly invasive routes, or ex vivo relying on the direct implantation of genetically modified cells into the brain. Here we provide evidence for a novel, noninvasive approach for targeting potential therapeutic factors to the CNS. Genetically-modified hematopoietic cells enter the CNS and differentiate into microglia after bone-marrow transplantation. Up to a quarter of the regional microglial population is donor-derived by four months after transplantation. Microglial engraftment is enhanced by neuropathology, and gene-modified myeloid cells are specifically attracted to the sites of neuronal damage. Thus, microglia may serve as vehicles for gene delivery to the nervous system.

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Figure 1: Reconstitution of hematopoiesis with GFP-expressing peripheral-blood cell progeny in lethally irradiated mice after transplantation of GFP-transduced BM.
Figure 2: Engraftment of BM-derived cells in the brains of mice transplanted with GFP-marked hematopoietic cells.
Figure 3: Microglial engraftment following transient focal cerebral ischemia.
Figure 4: Microglial engraftment following ff-t and facial nerve axotomy.

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Acknowledgements

We thank P. Grämmel, D. Büringer, K. Brückner, S. Bauer and A. Sittler for their assistance. The work was partly supported by DFG and the Schilling foundation.

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Correspondence to Josef Priller.

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Priller, J., Flügel, A., Wehner, T. et al. Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment. Nat Med 7, 1356–1361 (2001). https://doi.org/10.1038/nm1201-1356

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