Long term survival and limited migration of genetically modified monocytes/macrophages grafted into the mouse brain

Chamsy Sarkis, Gabriel Gras, Françoise Sanchez, Jacques Mallet, Ché Serguera

CEA, Institute of Emerging Diseases and Innovative Therapies, Division of Immuno-Virology, UMR E1 CEA and University Paris South, Fontenay-aux Roses, France.
Centre d’Etudes d’Agents Pathogènes et Biotechnologies pour la Santé (CPBS), UMR 5236, Montpellier, France.
Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, Equipe de Biotechnologie et Biothérapie, H?pital Pitié- Salpêtrière, Paris, France.
Laboratoire de Modélisation des Biothérapies, Groupe INSERM U986, MIRCen, CEA, Fontenay-aux Roses, France.

DOI: 10.4236/jbise.2013.65071                

Abstract

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.

Keywords

Adenoviral Vector; Human Myeloid Cells; β-Glucuronidase; Ex Vivo Gene Therapy; Neurotransplantation

Conflicts of Interest

The authors declare no conflicts of interest.

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