Reporter gene-expressing bone marrow-derived stromal cells are immune-tolerated following implantation in the central nervous system of syngeneic immunocompetent mice
Tóm tắt
Cell transplantation is likely to become an important therapeutic tool for the treatment of various traumatic and ischemic injuries to the central nervous system (CNS). However, in many pre-clinical cell therapy studies, reporter gene-assisted imaging of cellular implants in the CNS and potential reporter gene and/or cell-based immunogenicity, still remain challenging research topics. In this study, we performed cell implantation experiments in the CNS of immunocompetent mice using autologous (syngeneic) luciferase-expressing bone marrow-derived stromal cells (BMSC-Luc) cultured from ROSA26-L-S-L-Luciferase transgenic mice, and BMSC-Luc genetically modified using a lentivirus encoding the enhanced green fluorescence protein (eGFP) and the puromycin resistance gene (Pac) (BMSC-Luc/eGFP/Pac). Both reporter gene-modified BMSC populations displayed high engraftment capacity in the CNS of immunocompetent mice, despite potential immunogenicity of introduced reporter proteins, as demonstrated by real-time bioluminescence imaging (BLI) and histological analysis at different time-points post-implantation. In contrast, both BMSC-Luc and BMSC-Luc/eGFP/Pac did not survive upon intramuscular cell implantation, as demonstrated by real-time BLI at different time-points post-implantation. In addition, ELISPOT analysis demonstrated the induction of IFN-γ-producing CD8+ T-cells upon intramuscular cell implantation, but not upon intracerebral cell implantation, indicating that BMSC-Luc and BMSC-Luc/eGFP/Pac are immune-tolerated in the CNS. However, in our experimental transplantation model, results also indicated that reporter gene-specific immune-reactive T-cell responses were not the main contributors to the immunological rejection of BMSC-Luc or BMSC-Luc/eGFP/Pac upon intramuscular cell implantation. We here demonstrate that reporter gene-modified BMSC derived from ROSA26-L-S-L-Luciferase transgenic mice are immune-tolerated upon implantation in the CNS of syngeneic immunocompetent mice, providing a research model for studying survival and localisation of autologous BMSC implants in the CNS by real-time BLI and/or histological analysis in the absence of immunosuppressive therapy.
Tài liệu tham khảo
citation_journal_title=Nat Med; citation_title=Neuronal replacement from endogenous precursors in the adult brain after stroke; citation_author=A Arvidson, T Collin, D Kirik, Z Kokaia, O Lindvall; citation_volume=8; citation_publication_date=2002; citation_pages=963-970; citation_doi=10.1038/nm747; citation_id=CR1
citation_journal_title=Curr Opin Neurobiol; citation_title=Neurogenesis after ischaemic brain insults; citation_author=Z Kokaia, O Lindvall; citation_volume=13; citation_publication_date=2003; citation_pages=127-132; citation_doi=10.1016/S0959-4388(03)00017-5; citation_id=CR2
citation_journal_title=Regen Med; citation_title=Transplanted neural progenitor cells survive and differentiate but achieve limited functional recovery in the lesioned adult rat spinal cord; citation_author=DJ Webber, EJ Bradbury, SB McMahon, SL Minger; citation_volume=2; citation_publication_date=2007; citation_pages=929-945; citation_doi=10.2217/17460751.2.6.929; citation_id=CR3
citation_journal_title=Biomed Environ Sci; citation_title=Induction of functional recovery by co-transplantation of neural stem cells and Schwann cells in a rat spinal cord contusion injury model; citation_author=J Li, CR Sun, H Zhang, KS Tsang, JH Li, SD Zhang, YH An; citation_volume=20; citation_publication_date=2007; citation_pages=242-249; citation_id=CR4
citation_journal_title=Philos Trans R Soc Lond B Biol Sci; citation_title=Neurodegeneration and cell replacement; citation_author=BK Ormerod, TD Palmer, MA Caldwell; citation_volume=363; citation_publication_date=2008; citation_pages=153-170; citation_doi=10.1098/rstb.2006.2018; citation_id=CR5
citation_journal_title=Curr Opin Neurol; citation_title=Stem cell transplantation for neurodegenerative diseases; citation_author=AE Rosser, R Zietlow, SB Dunnett; citation_volume=20; citation_publication_date=2007; citation_pages=688-692; citation_doi=10.1097/WCO.0b013e3282f132fc; citation_id=CR6
citation_journal_title=Spinal Cord; citation_title=Can cell therapy heal a spinal cord injury?; citation_author=MW Ronsyn, ZN Berneman, VF Van Tendeloo, PG Jorens, P Ponsaerts; citation_volume=46; citation_publication_date=2008; citation_pages=532-539; citation_doi=10.1038/sc.2008.13; citation_id=CR7
citation_journal_title=Exp Neurol; citation_title=BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury; citation_author=P Lu, LL Jones, MH Tuszynski; citation_volume=191; citation_publication_date=2005; citation_pages=344-360; citation_doi=10.1016/j.expneurol.2004.09.018; citation_id=CR8
citation_journal_title=Eur J Neurosci; citation_title=Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury; citation_author=A Bakshi, S Shimizu, CA Keck, S Cho, DG LeBold, D Morales, E Arenas, EY Snyder, DJ Watson, TK McIntosh; citation_volume=23; citation_publication_date=2006; citation_pages=2119-2134; citation_doi=10.1111/j.1460-9568.2006.04743.x; citation_id=CR9
citation_journal_title=Mol Ther; citation_title=Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model; citation_author=K Kurozumi, K Nakamura, T Tamiya, Y Kawano, K Ishii, M Kobune, S Hirai, H Uchida, K Sasaki, Y Ito, K Kato, O Honmou, K Houkin, I Date, H Hamada; citation_volume=11; citation_publication_date=2005; citation_pages=96-104; citation_doi=10.1016/j.ymthe.2004.09.020; citation_id=CR10
citation_journal_title=BMC Biotechnology; citation_title=Plasmid-based genetic modification of human bone marrow-derived stromal cells: analysis of cell survival and transgene expression after transplantation in rat spinal cord; citation_author=MW Ronsyn, J Daans, G Spaepen, S Chatterjee, K Vermeulen, P D'Haese, VF Van Tendeloo, E Van Marck, D Ysebaert, ZN Berneman, PG Jorens, P Ponsaerts; citation_volume=7; citation_publication_date=2007; citation_pages=90; citation_doi=10.1186/1472-6750-7-90; citation_id=CR11
citation_journal_title=Eur J Nucl Med Mol Imaging; citation_title=Dynamic bioluminescence imaging for quantitative tumour burden assessment using IV or IP administration of D: -luciferin: effect on intensity, time kinetics and repeatability of photon emission; citation_author=M Keyaerts, J Verschueren, TJ Bos, LO Tchouate-Gainkam, C Peleman, K Breckpot, C Vanhove, V Caveliers, A Bossuyt, T Lahoutte; citation_volume=35; citation_publication_date=2008; citation_pages=999-1007; citation_doi=10.1007/s00259-007-0664-2; citation_id=CR12
citation_journal_title=J Neurochem; citation_title=Optical bioluminescence imaging of human ES cell progeny in the rodent CNS; citation_author=MS Bradbury, G Panagiotakos, BK Chan, M Tomishima, P Zanzonico, J Vider, V Ponomarev, L Studer, V Tabar; citation_volume=102; citation_publication_date=2007; citation_pages=2029-2039; citation_doi=10.1111/j.1471-4159.2007.04681.x; citation_id=CR13
citation_journal_title=Neuroimag; citation_title=In vivo and ex vivo MRI detection of localized and disseminated neural stem cell grafts in the mouse brain; citation_author=S Magnitsky, DJ Watson, RM Walton, S Pickup, JW Bulte, JH Wolfe, H Poptani; citation_volume=26; citation_publication_date=2005; citation_pages=744-754; citation_doi=10.1016/j.neuroimage.2005.02.029; citation_id=CR14
citation_journal_title=Mol Imaging; citation_title=Comparison of transfection agents in forming complexes with ferumoxides, cell labelling efficiency, and cellular viability; citation_author=AS Arbab, GT Yocum, LB Wilson, A Parwana, EK Jordan, H Kalish, JA Frank; citation_volume=3; citation_publication_date=2004; citation_pages=24-32; citation_doi=10.1162/153535004773861697; citation_id=CR15
citation_journal_title=Gene Ther; citation_title=Immunogenicity of enhanced green fluorescent protein (EGFP) in BALB/c mice: identification of an H2-Kd-restricted CTL epitope; citation_author=A Gambotto, G Dworacki, V Cicinnati, T Kenniston, J Steitz, T Tüting, PD Robbins, AB DeLeo; citation_volume=7; citation_publication_date=2000; citation_pages=2036-2040; citation_doi=10.1038/sj.gt.3301335; citation_id=CR16
citation_journal_title=Gene Ther; citation_title=Immune response to green fluorescent protein: implications for gene therapy; citation_author=R Stripecke, M Carmen Villacres, D Skelton, N Satake, S Halene, D Kohn; citation_volume=6; citation_publication_date=1999; citation_pages=1305-1312; citation_doi=10.1038/sj.gt.3300951; citation_id=CR17
citation_journal_title=Transplantation; citation_title=Firefly rats as an organ/cellular source for long-term in vivo bioluminescent imaging; citation_author=Y Hakamata, T Murakami, E Kobayashi; citation_volume=81; citation_publication_date=2006; citation_pages=1179-1184; citation_doi=10.1097/01.tp.0000203137.06587.4a; citation_id=CR18
citation_journal_title=J Control Release; citation_title=Optimisation of intradermal DNA electrotransfer for immunisation; citation_author=G Vandermeulen, E Staes, ML Vanderhaeghen, MF Bureau, D Scherman, V Préat; citation_volume=124; citation_publication_date=2007; citation_pages=81-87; citation_doi=10.1016/j.jconrel.2007.08.010; citation_id=CR19
citation_journal_title=Mol Imaging; citation_title=Mouse reporter strain for noninvasive bioluminescent imaging of cells that have undergone Cre-mediated recombination; citation_author=M Safran, WY Kim, AL Kung, JW Horner, RA DePinho, WG Kaelin; citation_volume=2; citation_publication_date=2003; citation_pages=297-302; citation_doi=10.1162/153535003322750637; citation_id=CR20
citation_journal_title=Blood; citation_title=Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential; citation_author=A Peister, JA Mellad, BL Larson, BM Hall, LF Gibson, DJ Prockop; citation_volume=103; citation_publication_date=2004; citation_pages=1662-1668; citation_doi=10.1182/blood-2003-09-3070; citation_id=CR21
citation_journal_title=Biochem Biophys Res Commun; citation_title=Efficient removal of LoxP-flanked genes by electroporation of Cre recombinase mRNA; citation_author=D Van den Plas, P Ponsaerts, V Van Tendeloo, DR Van Bockstaele, ZN Berneman, J Merregaert; citation_volume=305; citation_publication_date=2003; citation_pages=10-15; citation_doi=10.1016/S0006-291X(03)00669-7; citation_id=CR22
citation_journal_title=Gene Ther; citation_title=Messenger RNA electroporation is highly efficient in mouse embryonic stem cells: successful FLPe- and Cre-mediated recombination; citation_author=P Ponsaerts, JP Brown, D Van den Plas, L Van den Eeden, DR Van Bockstaele, PG Jorens, VF Van Tendeloo, J Merregaert, PB Singh, ZN Berneman; citation_volume=11; citation_publication_date=2004; citation_pages=1606-1610; citation_doi=10.1038/sj.gt.3302342; citation_id=CR23
citation_journal_title=Gene Ther; citation_title=Optimized lentiviral vector production and purification procedure prevents immune response after transduction of mouse brain; citation_author=V Baekelandt, K Eggermont, M Michiels, B Nuttin, Z Debyser; citation_volume=10; citation_publication_date=2003; citation_pages=1933-1940; citation_doi=10.1038/sj.gt.3302094; citation_id=CR24
citation_journal_title=J Gene Med; citation_title=Upscaling of lentiviral vector production by tangential flow filtration; citation_author=M Geraerts, M Michiels, V Baekelandt, Z Debyser, R Gijsbers; citation_volume=7; citation_publication_date=2005; citation_pages=1299-1310; citation_doi=10.1002/jgm.778; citation_id=CR25
citation_journal_title=Gene Ther; citation_title=5-Azacytidine prevents transgene methylation in vivo; citation_author=M Di Ianni, A Terenzi, K Perruccio, R Ciurnelli, F Lucheroni, R Benedetti, MF Martelli, A Tabilio; citation_volume=6; citation_publication_date=1999; citation_pages=703-707; citation_doi=10.1038/sj.gt.3300848; citation_id=CR26
citation_journal_title=Blood; citation_title=Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells; citation_author=VF Van Tendeloo, P Ponsaerts, F Lardon, G Nijs, M Lenjou, C Van Broeckhoven, DR Van Bockstaele, ZN Berneman; citation_volume=98; citation_publication_date=2001; citation_pages=49-56; citation_doi=10.1182/blood.V98.1.49; citation_id=CR27
citation_journal_title=J Immunol; citation_title=Messenger RNA electroporation of human monocytes, followed by rapid in vitro differentiation, leads to highly stimulatory antigen-loaded mature dendritic cells; citation_author=P Ponsaerts, G Van den Bosch, N Cools, A Van Driessche, G Nijs, M Lenjou, F Lardon, C Van Broeckhoven, DR Van Bockstaele, ZN Berneman, VF Van Tendeloo; citation_volume=169; citation_publication_date=2002; citation_pages=1669-1675; citation_doi=10.4049/jimmunol.169.4.1669; citation_id=CR28
citation_journal_title=Leukemia; citation_title=RNA-based gene transfer for adult stem cells and T cells; citation_author=E Smits, P Ponsaerts, M Lenjou, G Nijs, DR Van Bockstaele, ZN Berneman, VF Van Tendeloo; citation_volume=18; citation_publication_date=2004; citation_pages=1898-1902; citation_doi=10.1038/sj.leu.2403463; citation_id=CR29
citation_journal_title=J Cell Mol Med; citation_title=mRNA-mediated gene delivery into human progenitor cells promotes highly efficient protein expression; citation_author=JM Wiehe, P Ponsaerts, MT Rojewski, JM Homann, J Greiner, D Kronawitter, H Schrezenmeier, V Hombach, M Wiesneth, O Zimmermann, J Torzewski; citation_volume=11; citation_publication_date=2007; citation_pages=521-530; citation_doi=10.1111/j.1582-4934.2007.00038.x; citation_id=CR30
citation_journal_title=Leukemia; citation_title=Modulation of cellular behavior by exogenous messenger RNA; citation_author=P Ponsaerts, ZN Berneman; citation_volume=20; citation_publication_date=2006; citation_pages=767-769; citation_doi=10.1038/sj.leu.2404219; citation_id=CR31
citation_journal_title=Curr Opin Mol Ther; citation_title=mRNA-based gene transfer as a tool for gene and cell therapy; citation_author=VF Van Tendeloo, P Ponsaerts, ZN Berneman; citation_volume=9; citation_publication_date=2007; citation_pages=423-431; citation_id=CR32
citation_journal_title=J Inflamm (Lond); citation_title=Mesenchymal stem cells avoid allogeneic rejection; citation_author=JM Ryan, FP Barry, JM Murphy, BP Mahon; citation_volume=26; citation_publication_date=2005; citation_pages=8; citation_doi=10.1186/1476-9255-2-8; citation_id=CR33
citation_journal_title=Immunol Rev; citation_title=CNS immune privilege: hiding in plain sight; citation_author=MJ Carson, JM Doose, B Melchior, CD Schmid, CC Ploix; citation_volume=213; citation_publication_date=2006; citation_pages=48-65; citation_doi=10.1111/j.1600-065X.2006.00441.x; citation_id=CR34