In mammals, myeloid progenitors infiltrate the developing
central nervous system (CNS), through the immature blood-brain barrier (BBB), the
ventricular layer or the pial surface migrate and give rise to resident microglia. In the mature brain, however, the BBB hampers such recruitment from the blood-stream and long-term establishment
of blood borne myeloid cells in the CNS thus appears at best limited. Hematopoietic stem cell-derived microglia, nevertheless, represents a promising tool for
the correction of genetic deficits in the brain.
We thus investigated the fate of primary human monocytes, and monocyte-derived
macrophages, following transplantation into the adult mouse brain overpassing
the BBB. Furthermore, we documented the ability of such cells to deliver a lysosomal enzyme into the brain following genetic modification with a recombinant adenoviral vector carrying the human β-glucuronidase cDNA. When implanted into the mouse striatum, the engineered primary cells
survived and expressed the transgene for as much as 8 months. Moreover, the donor
cells could migrate out of the grafting site and settle along blood vessels or myelin
tracts although at limited distance. Migrating donor cells down-regulated the expression
of CD14 andHLA DR,
suggesting the adoption of a deactivated microglia-like phenotype. Our observations establish the ability of circulating mononuclear phagocytes to integrate into the brain after transplantation and express
a transgene on the long term. These cells might thus be employed for autologous
transplantation for the delivery of secreted therapeutic proteins in the
context of a wide range of brain affections.
Cite this paper
Sarkis, C. , Gras, G. , Sanchez, F. , Mallet, J. and Serguera, C. (2013) Long term survival and limited migration of genetically modified monocytes/macrophages grafted into the mouse brain. Journal of Biomedical Science and Engineering, 6, 561-571. doi: 10.4236/jbise.2013.65071.
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