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| 2. |
- Zhang, Yiqin, et al.
(författare)
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CNS progenitor cells promote a permissive environment for neurite outgrowth via a matrix metalloproteinase-2-dependent mechanism
- 2007
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Ingår i: The Journal of Neuroscience. - 1529-2401. ; 27:17, s. 4499-4506
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation of progenitor cells to the CNS has shown promise in neuronal and glial replacement and as a means of rescuing host neurons from apoptosis. Here we examined the effect of progenitor grafts on neurite extension in the degenerating retina of rd1 ( retinal degeneration 1) mice. Transplantation of retinal progenitor cells induced increased matrix metalloproteinase-2( MMP2) secretion, partly from activated glial cells, which was then activated by neuronally expressed MMP14. Active MMP2 resulted in proteolysis of the neurite outgrowth inhibitors CD44 and neurocan in the degenerative retina, allowing significantly increased neurite outgrowth across the border between abutting nondystrophic and rd1 retinas. Progenitor-induced enhancement of outgrowth was abrogated by an MMP inhibitor or by coculture with retinal explants from MMP2(-/-) mice. This study provides the first identification of an MMP2-dependent mechanism by which exogenous progenitor cells alter the host environment to promote neural regeneration. This suggests a novel therapeutic role for progenitor cells in the treatment of CNS degenerative diseases.
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| 3. |
- Klassen, Henry, et al.
(författare)
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Isolation of progenitor cells from GFP-Transgenic pigs and transplantation to the retina of allorecipients
- 2008
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Ingår i: Cloning and Stem Cells. - : Mary Ann Liebert Inc. - 1536-2302 .- 1557-7457. ; 10:3, s. 391-402
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Tidskriftsartikel (refereegranskat)abstract
- Work in rodents has demonstrated that progenitor transplantation can achieve limited photoreceptor replacement in the mammalian retina; however, replication of these findings on a clinically relevant scale requires a large animal model. To evaluate the ability of porcine retinal progenitor cells to survival as allografts and integrate into the host retinal architecture, we isolated donor cells from fetal green fluorescent protein (GFP)transgenic pigs. Cultures were propagated from the brain, retina, and corneo-scleral limbus. GFP expression rapidly increased with time in culture, although lower in conjunction with photoreceptor markers and filial fibrillary acid protein (GFAP), thus suggesting downregulation of GFP during differentiation. Following transplantation, GFP expression allowed histological visualization of integrated cells and extension of fine processes to adjacent plexiform layers. GFP expression in subretinal grafts was high in cells expressing vimentin and lower in cells expressing photoreceptor markers, again consistent with possible downregulation during differentiation. Cells survived transplantation to the injured retina of allorecipients at all time points examined (up to 10 weeks) in the absence of exogenous immune suppression without indications of rejection. These findings demonstrate the feasibility of allogeneic progenitor transplantation in a large mammal and the utility of the pig in ocular regeneration studies.
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| 4. |
- Klassen, Henry, et al.
(författare)
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Neural precursors isolated from the developing cat brain show retinal integration following transplantation to the retina of the dystrophic cat
- 2007
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Ingår i: Veterinary Ophthalmology. - : Wiley. - 1463-5216 .- 1463-5224. ; 10:4, s. 245-253
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Tidskriftsartikel (refereegranskat)abstract
- The cat has served as an important nonrodent research model for neurophysiology and retinal degenerative disease processes, yet very little is known about feline neural precursor cells. To culture these cells and evaluate marker expression, brains were dissected from 45-day-old fetuses, enzymatically dissociated, and grown in the presence of EGF, bFGF and PDGF. Expanded cells widely expressed nestin, Sox2, Ki-67, fusin (CXCR4) and vimentin, while subpopulations expressed A2B5, GFAP, or beta-III tubulin. Precursors prelabeled with BrdU and/or transduced with a recombinant lentivirus that expresses GFP were transplanted subretinally in five dystrophic Abyssinian cats. Two to 4 weeks following surgery, histology showed survival of grafted cells in three of the animals. Labeled cells were found in the neuroretina and RPE layer, as well as in the vitreous and the vicinity of Bruch's membrane. There was no evidence of an immunologic response in any of the eyes. Neural precursor cells can therefore be cultured from the developing cat brain and survive as allografts for up to 4 weeks without immune suppression. The feasibility of deriving and transplanting feline neural precursor cells, combined with the availability of the dystrophic Abyssinian cat, provide a new feline model system for the study of retinal repair.
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| 5. |
- Klassen, Henry, et al.
(författare)
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Progenitor cells from the porcine neural retina express photoreceptor markers after transplantation to the subretinal space of allorecipients
- 2007
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 25:5, s. 1222-1230
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Tidskriftsartikel (refereegranskat)abstract
- Work in rodents has shown that cultured retinal progenitor cells (RPCs) integrate into the degenerating retina, thus suggesting a potential strategy for treatment of similar degenerative conditions in humans. To demonstrate the relevance of the rodent work to large animals, we derived progenitor cells from the neural retina of the domestic pig and transplanted them to the laser-injured retina of allorecipients. Prior to grafting, immunocytochemical analysis showed that cultured porcine RPCs widely expressed neural cell adhesion molecule, as well as markers consistent with immature neural cells, including nestin, Sox2, and vimentin. Subpopulations expressed the neurodevelopmental markers CD-15, doublecortin, beta-III tubulin, and glial fibrillary acidic protein. Retina-specific markers expressed included the bipolar marker protein kinase C alpha and the photoreceptor-associated markers recoverin and rhodopsin. In addition, reverse transcription-polymerase chain reaction showed expression of the transcription factors Dach1, Hes1, Lhx2, Pax6, Six3, and Six6. Progenitor cells prelabeled with vital dyes survived as allografts in the subretinal space for up to 5 weeks (11 of 12 recipients) without exogenous immune suppression. Grafted cells expressed transducin, recoverin, and rhodopsin in the pig subretinal space, suggestive of differentiation into photoreceptors or, in a few cases, migrated into the neural retina and extended processes, the latter typically showing radial orientation. These results demonstrate that many of the findings seen with rodent RPCs can be duplicated in a large mammal. The pig offers a number of advantages over mice and rats, particularly in terms of functional testing and evaluation of the potential for clinical translation to human subjects.
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| 6. |
- Warfvinge, Karin, et al.
(författare)
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Retinal progenitor cell xenografts to the pig retina: immunological reactions.
- 2006
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Ingår i: Cell Transplantation. - 1555-3892. ; 15:7, s. 603-612
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the host response to murine retinal progenitor cells (RPCs) following transplantation to the subretinal space (SRS) of the pig. RPCs from GFP mice were transplanted subretinally in 18 nonimmunosuppressed normal or laser-treated pigs. Evaluation of the SRS was performed on hematoxylin-cosin (H&E)-stained sections. Serum samples were taken from naive and RPC-grafted pigs and mouse-reactive antibody responses were assessed. At 1 week, histology showed a few perivascular lymphocytes consistent with a mild retinal vasculitis, and depigmentation of the RPE with large numbers of mononuclear inflammatory cells in the choroid near the transplantation site. Large choroidal infiltrates were evident at 2-5 weeks. Serum from naive and RPC-xenografted pigs contained significant levels of preformed IgG and IgM antibodies against murine antigens. Xenogeneic RPCs transplanted to the porcine SRS induced mononuclear infiltration in the choroid with graft rejection occurring over 2-5 weeks. Serum analysis confirmed that mice and pigs are discordant species; however, a cell-mediated acute mechanism appears to be responsible, rather than an antibody-mediated rejection.
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| 7. |
- Warfvinge, Karin, et al.
(författare)
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Xenotransplantation of human neural progenitor cells to the subretinal space of nonimmunosuppressed pigs.
- 2011
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Ingår i: Journal of transplantation. - : Hindawi Limited. - 2090-0015 .- 2090-0007. ; 2011:Article ID 948740
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the feasibility of transplanting human neural progenitor cells (hNPCs) to the retina of nonimmunosuppressed pigs, cultured hNPCs were injected into the subretinal space of 5 adult pigs after laser burns were applied to promote donor cell integration. Postoperatively, the retinal vessels appeared normal without signs of exudation, bleeding, or subretinal elevation. Eyes were harvested at 10-28 days. H&E consistently showed mild retinal vasculitis, depigmentation of the RPE, and marked mononuclear cell infiltrate in the choroid adjacent to the site of transplantation. Human-specific antibodies revealed donor cells in the subretinal space at 10-13 days and smaller numbers within the retina on days 12 and 13, with evidence suggesting a limited degree of morphological integration; however, no cells remained at 4 weeks. The strong mononuclear cell reaction and loss of donor cells indicate that modulation of host immunity is likely necessary for prolonged xenograft survival in this model.
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