Effects of severity of host striatal damage on the morphological development of intrastriatal transplants in a rodent model of Huntington's disease: implications for timing of surgical intervention

Watts, Colin; Dunnett, Stephen B.

doi:10.3171/jns.1998.89.2.0267

Cited by 33 publications

(11 citation statements)

References 64 publications

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“…Conversely, when cells were grafted following an excitotoxic insult, they were massively present and distributed throughout the lesioned structure. Our observations are also in accordance with the general view that the environment of the diseased brain promotes the survival and migration of grafted stem cells (see Bjorklund and Stenevi, 1984;Sotelo and Alvarado-Mallart, 1987 but also Watts and Dunnett, 1998;Eglitis et al, 1999;Nishino et al, 2000;Mahmood et al, 2001;Imitola et al, 2004;Hill et al, 2004;Kelly et al, 2004;Geloso et al, 2007) and lead us to suggest that at least one factor present within the lesion core promotes the engraftment of these two types of exogenous stem cells of distinct embryonic origins. One such factor could be SCF, shown to be mitogen and chemoattractant for many cells in the hematopoietic system, with the ability to enhance the mobilization of peripheral blood progenitor cells (McNiece and Briddell, 1995;Glaspy, 1996) and to stimulate neurogenesis as well as the migration of endogenous neural stem cells in vivo (Jin et al, 2002;Sun et al, 2004).…”

Section: Discussionsupporting

confidence: 91%

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

Bantubungi

Blum

Cuvelier

et al. 2008

Molecular and Cellular Neuroscience

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Neural and mesenchymal stem cells have been proposed as alternative sources of cells for transplantation into the brain in neurodegenerative disorders. However, the endogenous factors controlling their engraftment within the injured parenchyma remain ill-defined. Here, we demonstrate significant engraftment of undifferentiated exogenous mesenchymal or neural stem cells throughout the lesioned area in a rat model for Huntington's disease, as late as 8 weeks post-transplantation. We show that stem cell factor (SCF), strongly up-regulated within host cells in the damaged striatum, is able to activate the SCF receptor c-kit and its signaling pathway and to promote the migration and proliferation of mesenchymal and neural stem cells in vitro. Furthermore, c-kit receptor blockade alters neural stem cell distribution within the lesioned striatum. Host SCF expression is observed in atypical cells expressing glial fibrillary acidic protein and doublecortin in the lesioned striatum and in migrating doublecortin-positive progenitors. Taken together, these data demonstrate that SCF produced in situ in the lesioned striatum is an important factor in promoting the engraftment of stem cells within the lesioned brain.

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Section: Discussionsupporting

confidence: 91%

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

Bantubungi

Blum

Cuvelier

et al. 2008

Molecular and Cellular Neuroscience

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“…Further experiments will be required to establish why cell body lesions of the striatum increase stem cell survival. However, it is possible that increasing the lesion size further may not be beneficial because previous reports suggest that there is a threshold above which damage to the striatum or hippocampus leads to a reduction in tissue graft survival (24,30).…”

Section: Discussionmentioning

confidence: 91%

“…Clearly, both the cell source and the host environment will dictate how and if the cells integrate and survive. Early studies where primary rodent fetal brain tissue (which contains a mixture of stem cells, progenitor cells and terminally differentiated cells) was grafted into the striatum have shown that mild to moderate lesions can significantly increase the survival of the transplants (30). This was presumably due to a combination of chemokine and growth factor release at the injury site supporting the new cells, in addition to the creation of more physical space within the brain due to the lesion.…”

Section: Introductionmentioning

confidence: 99%

Lesion-Induced Increase in Survival and Migration of Human Neural Progenitor Cells Releasing GDNF

et al. 2008

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The use of human neural progenitor cells (hNPC) has been proposed to provide neuronal replacement or astrocytes delivering growth factors for brain disorders such as Parkinson's and Huntington's disease. Success in such studies likely requires migration from the site of transplantation and integration into host tissue in the face of ongoing damage. In the current study, hNPC modified to release glial cell line derived neurotrophic factor (hNPC GDNF ) were transplanted into either intact or lesioned animals. GDNF release itself had no effect on the survival, migration or differentiation of the cells. The most robust migration and survival was found using a direct lesion of striatum (Huntington's model) with indirect lesions of the dopamine system (Parkinson's model) or intact animals showing successively less migration and survival. No lesion affected differentiation patterns. We conclude that the type of brain injury dictates migration and integration of hNPC which has important consequences when considering transplantation of these cells as a therapy for neurodegenerative diseases.

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“…24 The prosurvival effect of brain lesions has been reported. 25 However, it was no longer significant after differentiation into NPs, which apparently differ from early NPG in their sensitivity to extrinsic trophic factors or to transplantation.…”

Section: Seminatore Et Al Impact Of Ischemia On Hesc-neural Progenitorsmentioning

confidence: 99%

The Postischemic Environment Differentially Impacts Teratoma or Tumor Formation After Transplantation of Human Embryonic Stem Cell-Derived Neural Progenitors

Seminatore

Polentes²,

Ellman³

et al. 2010

Stroke

122

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Background and Purpose-Risk of tumorigenesis is a major obstacle to human embryonic and induced pluripotent stem cell therapy. Likely linked to the stage of differentiation of the cells at the time of implantation, formation of teratoma/tumors can also be influenced by factors released by the host tissue. We have analyzed the relative effects of the stage of differentiation and the postischemic environment on the formation of adverse structures by transplanted human embryonic stem cell-derived neural progenitors. Methods-Four differentiation stages were identified on the basis of quantitative polymerase chain reaction expression of pluripotency, proliferation, and differentiation markers. Neural progenitors were transplanted at these 4 stages into rats with no, small, or large middle cerebral artery occlusion lesions. The fate of each transplant was compared with their pretransplantation status 1 to 4 months posttransplantation. Results-The influence of the postischemic environment was limited to graft survival and occurrence of nonneuroectodermal structures after transplantation of very immature neural progenitors. Both effects were lost with differentiation. We identified a particular stage of differentiation characterized in vitro by a rebound of proliferative activity that produced highly proliferative grafts susceptible to threaten surrounding host tissues. Conclusion-The effects of the ischemic environment on the formation of teratoma by transplanted human embryonic stem cell-derived neural progenitors are limited to early differentiation stages that will likely not be used for stem cell therapy. In contrast, hyperproliferation observed at later stages of differentiation corresponds to an intrinsic activity that should be monitored to avoid tumorigenesis. (Stroke. 2010;41:153-159.)

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Effects of severity of host striatal damage on the morphological development of intrastriatal transplants in a rodent model of Huntington's disease: implications for timing of surgical intervention

Abstract: These results have significant implications for the timing of surgical intervention and patient selection with respect to current and future clinical trials of striatal transplantation in the treatment of Huntington's disease.

Cited by 33 publications

References 64 publications

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease

Lesion-Induced Increase in Survival and Migration of Human Neural Progenitor Cells Releasing GDNF

The Postischemic Environment Differentially Impacts Teratoma or Tumor Formation After Transplantation of Human Embryonic Stem Cell-Derived Neural Progenitors

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