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Chondroitin sulfate proteoglycans and microglia prevent migration and integration of grafted Muller stem cells into degenerating retina

Singhal, Shweta; Lawrence, Jean M; Bhatia, Bhairavi; Ellis, James S; Kwan, Anthony S; MacNeil, Angus; Luthert, Philip J; Fawcett, James W; Perez, Maria Thereza LU and Khaw, Peng T, et al. (2008) In Stem Cells 26(4). p.1074-1082
Abstract
At present, there are severe limitations to the successful migration and integration of stem cells transplanted into the degenerated retina to restore visual function. This study investigated the potential role of chondroitin sulfate proteoglycans (CSPGs) and microglia in the migration of human Muller glia with neural stem cell characteristics following subretinal injection into the Lister hooded (LH) and Royal College of Surgeons (RCS) rat retinae. Neonate LH rat retina showed minimal baseline microglial accumulation (CD68-positive cells) that increased significantly 2 weeks after transplantation (p <.001), particularly in the ganglion cell layer (GCL) and inner plexiform layer. In contrast, nontransplanted 5-week-old RCS rat retina... (More)
At present, there are severe limitations to the successful migration and integration of stem cells transplanted into the degenerated retina to restore visual function. This study investigated the potential role of chondroitin sulfate proteoglycans (CSPGs) and microglia in the migration of human Muller glia with neural stem cell characteristics following subretinal injection into the Lister hooded (LH) and Royal College of Surgeons (RCS) rat retinae. Neonate LH rat retina showed minimal baseline microglial accumulation (CD68-positive cells) that increased significantly 2 weeks after transplantation (p <.001), particularly in the ganglion cell layer (GCL) and inner plexiform layer. In contrast, nontransplanted 5-week-old RCS rat retina showed considerable baseline microglial accumulation in the outer nuclear layer (ONL) and photoreceptor outer segment debris zone (DZ) that further increased (p <.05) throughout the retina 2 weeks after transplantation. Marked deposition of the N-terminal fragment of CSPGs, as well as neurocan and versican, was observed in the DZ of 5-week-old RCS rat retinae, which contrasted with the limited expression of these proteins in the GCL of the adult and neonate LH rat retinae. Staining for CSPGs and CD68 revealed colocalization of these two molecules in cells infiltrating the ONL and DZ of the degenerating RCS rat retina. Enhanced immune suppression with oral prednisolone and intraperitoneal injections of indomethacin caused a reduction in the number of microglia but did not facilitate Muller stem cell migration. However, injection of cells with chondroitinase ABC combined with enhanced immune suppression caused a dramatic increase in the migration of Muller stem cells into all the retinal cell layers. These observations suggest that both microglia and CSPGs constitute a barrier for stem cell migration following transplantation into experimental models of retinal degeneration and that control of matrix deposition and the innate microglial response to neural retina degeneration may need to be addressed when translating cell-based therapies to treat human retinal disease. (Less)
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publication status
published
subject
keywords
tissue regeneration tissue-specific stem cells, experimental models, stem cell transplantation, adult stem cells, cell migration
in
Stem Cells
volume
26
issue
4
pages
1074 - 1082
publisher
AlphaMed Press
external identifiers
  • wos:000255000000025
  • scopus:49249120572
ISSN
1549-4918
DOI
10.1634/stemcells.2007-0898
language
English
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yes
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b4e54f7e-b764-46e0-9e39-9677889b69d3 (old id 1205619)
date added to LUP
2008-09-19 11:33:27
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2017-10-31 15:21:25
@article{b4e54f7e-b764-46e0-9e39-9677889b69d3,
  abstract     = {At present, there are severe limitations to the successful migration and integration of stem cells transplanted into the degenerated retina to restore visual function. This study investigated the potential role of chondroitin sulfate proteoglycans (CSPGs) and microglia in the migration of human Muller glia with neural stem cell characteristics following subretinal injection into the Lister hooded (LH) and Royal College of Surgeons (RCS) rat retinae. Neonate LH rat retina showed minimal baseline microglial accumulation (CD68-positive cells) that increased significantly 2 weeks after transplantation (p &lt;.001), particularly in the ganglion cell layer (GCL) and inner plexiform layer. In contrast, nontransplanted 5-week-old RCS rat retina showed considerable baseline microglial accumulation in the outer nuclear layer (ONL) and photoreceptor outer segment debris zone (DZ) that further increased (p &lt;.05) throughout the retina 2 weeks after transplantation. Marked deposition of the N-terminal fragment of CSPGs, as well as neurocan and versican, was observed in the DZ of 5-week-old RCS rat retinae, which contrasted with the limited expression of these proteins in the GCL of the adult and neonate LH rat retinae. Staining for CSPGs and CD68 revealed colocalization of these two molecules in cells infiltrating the ONL and DZ of the degenerating RCS rat retina. Enhanced immune suppression with oral prednisolone and intraperitoneal injections of indomethacin caused a reduction in the number of microglia but did not facilitate Muller stem cell migration. However, injection of cells with chondroitinase ABC combined with enhanced immune suppression caused a dramatic increase in the migration of Muller stem cells into all the retinal cell layers. These observations suggest that both microglia and CSPGs constitute a barrier for stem cell migration following transplantation into experimental models of retinal degeneration and that control of matrix deposition and the innate microglial response to neural retina degeneration may need to be addressed when translating cell-based therapies to treat human retinal disease.},
  author       = {Singhal, Shweta and Lawrence, Jean M and Bhatia, Bhairavi and Ellis, James S and Kwan, Anthony S and MacNeil, Angus and Luthert, Philip J and Fawcett, James W and Perez, Maria Thereza and Khaw, Peng T and Limb, Astrid},
  issn         = {1549-4918},
  keyword      = {tissue regeneration tissue-specific stem cells,experimental models,stem cell transplantation,adult stem cells,cell migration},
  language     = {eng},
  number       = {4},
  pages        = {1074--1082},
  publisher    = {AlphaMed Press},
  series       = {Stem Cells},
  title        = {Chondroitin sulfate proteoglycans and microglia prevent migration and integration of grafted Muller stem cells into degenerating retina},
  url          = {http://dx.doi.org/10.1634/stemcells.2007-0898},
  volume       = {26},
  year         = {2008},
}