Share This Article:

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

Abstract Full-Text HTML XML Download Download as PDF (Size:523KB) PP. 561-571
DOI: 10.4236/jbise.2013.65071    3,375 Downloads   4,901 Views   Citations

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.

Conflicts of Interest

The authors declare no conflicts of interest.

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.

References

[1] Kennedy, D.W. and Abkowitz, J.L. (1998) Mature monocytic cells enter tissues and engraft. Proceedings of the National Academy of Sciences of the United States of America, 95, 14944-14949. doi:10.1073/pnas.95.25.14944
[2] Naito, M., et al. (1996) Development, differentiation and phénotipique heterogeneity of murine macrophages. Journal of Leukocyte Biology, 59, 133-137.
[3] Murray, P.J. and Wynn, T.A. (2011) Protective and pathogenic functions of macrophage subsets. Nature Reviews Immunology, 11, 723-737. doi:10.1038/nri3073
[4] Ransohoff, R.M. and Perry, V.H. (2009) Microglial physiology: Unique stimuli, specialized responses. Annual Review of Immunology, 27, 119-145. doi:10.1146/annurev.immunol.021908.132528
[5] Ajami, B., et al. (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nature Neuroscience, 14, 1142-1149. doi:10.1038/nn.2887
[6] Ajami, B., et al. (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neuroscience, 10, 1538-1543. doi:10.1038/nn2014
[7] Cartier, N., et al. (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science, 326, 818-823. doi:10.1126/science.1171242
[8] Faradji, A., et al. (1991) Phase I trial of intravenous infusion of ex-vivo-activated autologous blood-derived macrophages in patients with non-small-cell lung cancer: Toxicity and immunomodulatory effects. Cancer Immunology, Immunotherapy, 33, 319-326. doi:10.1007/BF01756597
[9] Parrish, E.P., et al. (1996) Targeting widespread sites of damage in dystrophic muscle: Engrafted macrophages as potential shuttles. Gene Therapy, 3, 13-20.
[10] Dou, H., et al. (2009) Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuro AIDS. Journal of Immunology, 183, 661-669. doi:10.4049/jimmunol.0900274
[11] Freeman, B.J., et al. (1999) Behavior and therapeutic efficacy of beta-glucuronidase-positive mononuclear phagocytes in a murine model of mucopolysaccharidosis type VII. Blood, 94, 2142-2150.
[12] Ohashi, T., et al. (2000) Reduction of lysosomal storage in murine mucopolysaccharidosis type VII by transplanttation of normal and genetically modified macrophages. Blood, 95, 3631-3633.
[13] Mordelet, E., et al. (2002) Brain engraftment of autologous macrophages transduced with a lentiviral flap vector: An approach to complement brain dysfunctions. Gene Therapy, 9, 46-52. doi:10.1038/sj.gt.3301591
[14] Oehmichen, M., et al. (1979) Features and distribution of intracerebrally injected peritoneal macrophages. Experimentelle Pathologie, 17, 71-76.
[15] Walczak, P., et al. (2004) Do hematopoietic cells exposed to a neurogenic environment mimic properties of endogenous neural precursors? Journal of Neuroscience Research, 76, 244-254. doi:10.1002/jnr.20042
[16] Franzen, R., et al. (1998) Effects of macrophage transplantation in the injured adult rat spinal cord: A combined immunocytochemical and biochemical study. Journal of Neuroscience Research, 51, 316-327. doi:10.1002/(SICI)1097-4547(19980201)51:3<316::AID-JNR5>3.0.CO;2-J
[17] Lazarov-Spiegler, O., et al. (1996) Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB Journal, 10, 1296-1302.
[18] Brynskikh, A.M., et al. (2010) Macrophage delivery of therapeutic nanozymes in a murine model of Parkinson’s disease. Nanomedicine (Lond), 5, 379-396.
[19] Krall, W.J., et al. (1994) Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine marrow transplantation. Blood, 83, 2737-2748.
[20] Gorantla, S., et al. (2006) Quantitative magnetic resonance and SPECT imaging for macrophage tissue migration and nanoformulated drug delivery. Journal of Leukocyte Biology, 80, 1165-1174. doi:10.1189/jlb.0206110
[21] Mildner, A., et al. (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nature Neuroscience, 10, 1544-1553.
[22] D’Mello, C., Le, T. and Swain, M.G. (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. Journal of Neuroscience, 29, 20892102. doi:10.1523/JNEUROSCI.3567-08.2009
[23] Djukic, M., et al. (2006) Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain, 129, 2394-2403. doi:10.1093/brain/awl206
[24] Flugel, A., et al. (2001) Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy. Journal of Neuroscience Research, 66, 74-82. doi:10.1002/jnr.1198
[25] Serguera, C., et al. (2001) Primary adult human astrocytes as an ex vivo vehicle for beta-glucuronidase delivery in the brain. Molecular Therapy, 3, 875-881. doi:10.1006/mthe.2001.0319
[26] Ghodsi, A., et al. (1998) Extensive beta-glucuronidase activity in murine central nervous system after adenovirus-mediated gene transfer to brain. Human Gene Therapy, 9, 2331-2340. doi:10.1089/hum.1998.9.16-2331
[27] Palucka, K.A., et al. (1998) Dendritic cells as the terminal stage of monocyte differentiation. Journal of Immunology, 160, 4587-4595.
[28] Benhamida, S., et al. (2003) Transduced CD34+ cells from adrenoleukodystrophy patients with HIV-derived vector mediate long-term engraftment of NOD/SCID mice. Molecular Therapy, 7, 317-324. doi:10.1016/S1525-0016(03)00002-9
[29] Frankel, H.A., Glaser, J.H. and Sly, W.S. (1977) Human beta-glucuronidase. I. Recognition and uptake by animal fibroblasts suggests animal models for enzyme replacement studies. Pediatric Research, 11, 811-816. doi:10.1203/00006450-197707000-00007
[30] Taylor, R.M. and Wolfe, J.H. (1997) Decreased lysosomal storage in the adult MPS VII mouse brain in the vicinity of grafts of retroviral vector corrected fibroblasts secreting high levels of β-glucuronidase. Nature Medicine, 3, 771-775. doi:10.1038/nm0797-771
[31] Laszlo, D.J., et al. (1993) Development of functional diversity in mouse macrophages. Mutual exclusion of two phenotypic states. American Journal of Pathology, 143, 587-597.
[32] Szaniawski, W. (1976) Localizations of beta-glucuronidase activity in sections and cultures of human gliomas. Acta Neuropathologica, 34, 47-54. doi:10.1007/BF00684943
[33] Takahashi, H., et al. (2008) Involvement of heparanase in migration of microglial cells. Biochimica et Biophysica Acta, 1780, 709-715. doi:10.1016/j.bbagen.2007.12.014
[34] Grossmann, R., et al. (2002) Juxtavascular microglia migrate along brain microvessels following activation during early postnatal development. Glia, 37, 229-240. doi:10.1002/glia.10031
[35] Azizi, S.A., et al. (1998) Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats—Similarities to astrocyte grafts. Proceedings of the National Academy of Sciences of the United States of America, 95, 3908-3913. doi:10.1073/pnas.95.7.3908
[36] Pundt, L.L., Kondoh, T. and Low, W.C. (1995) The fate of human glial cells following transplantation in normal rodents and rodent models of neurodegenerative disease. Brain Research, 695, 25-36. doi:10.1016/0006-8993(95)00753-D
[37] Kosuga, M., et al. (2001) Engraftment of genetically engineered amniotic epithelial cells corrects lysosomal storage in multiple areas of the brain in mucopolysaccharidosis type VII mice. Molecular Therapy, 3, 139-148. doi:10.1006/mthe.2000.0234
[38] Hess, D.C., et al. (2004) Hematopoietic origin of microglial and perivascular cells in brain. Experimental Neurology, 186, 134-144. doi:10.1016/j.expneurol.2003.11.005
[39] Cuadros, M.A. and Navascues, J. (1998) The origin and differentiation of microglial cells during development. Progress in Neurobiology, 56, 173-189. doi:10.1016/S0301-0082(98)00035-5
[40] Conductier, G., et al. (2010) The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. Journal of Neuroimmunology, 224, 93-100.sdoi:10.1016/j.jneuroim.2010.05.010
[41] Dzenko, K.A., et al. (2001) The chemokine receptor CCR2 mediates the binding and internalization of monocyte chemoattractant protein-1 along brain microvessels. Journal of Neuroscience, 21, 9214-9123.
[42] Carey, B., et al. (2007) PU.1 redirects adenovirus to lysosomes in alveolar macrophages, uncoupling internalization from infection. Journal of Immunology, 178, 24402447.
[43] Porcheray, F., et al. (2005) Macrophage activation switching: An asset for the resolution of inflammation. Clinical & Experimental Immunology, 142, 481-489.

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.