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Neural Stem and Progenitor Cells as a Tool for Tissue Regeneration
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Karin Forsberg-Nilsson)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neural stem and progenitor cells (NSPC) can differentiate to neurons and glial cells. NSPC are easily propagated in vitro and are therefore an attractive tool for tissue regeneration. Traumatic brain injury (TBI) is a common cause for death and disabilities. A fundamental problem following TBI is tissue loss. Animal studies aiming at cell replacement have encountered difficulties in achieving sufficient graft survival and differentiation. To improve outcome of grafted cells after experimental TBI (controlled cortical impact, CCI) in mice, we compared two transplantation settings. NSPC were transplanted either directly upon CCI to the injured parenchyma, or one week after injury to the contralateral ventricle. Enhanced survival of transplanted cells and differentiation were seen when cells were deposited in the ventricle. To further enhance cell survival, efforts were made to reduce the inflammatory response to TBI by administration of ibuprofen to mice that had been subjected to CCI. Inflammation was reduced, as monitored by a decrease in inflammatory markers. Cell survival as well as differentiation to early neuroblasts seemed to be improved.

To device a 3D system for future transplantation studies, NSPC from different ages were cultured in a hydrogel consisting of hyaluronan and collagen. Cells survived and proliferated in this culturing condition and the greatest neuronal differentiating ability was seen in cells from the newborn mouse brain.

NSPC were also used in a model of peripheral nervous system injury, and xeno-transplanted to rats where the dorsal root ganglion had been removed. Cells survived and differentiated to neurons and glia, furthermore demonstrating their usefulness as a tool for tissue regeneration.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2009. , p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 500
Keywords [en]
traumatic brain injury, neural stem cells, transplantation, CNS, PNS, progenitor cells, inflammation, CCI
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Neurosurgery; Medical Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-110095ISBN: 978-91-554-7658-8 (print)OAI: oai:DiVA.org:uu-110095DiVA, id: diva2:275184
Public defence
2009-12-17, B42, Husargatan 3, BMC, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2009-11-26 Created: 2009-11-03 Last updated: 2009-11-26Bibliographically approved
List of papers
1. Enhanced neuronal differentiation in a three-dimensional collagen-hyaluronan matrix
Open this publication in new window or tab >>Enhanced neuronal differentiation in a three-dimensional collagen-hyaluronan matrix
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2007 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 85, no 10, p. 2138-2146Article in journal (Refereed) Published
Abstract [en]

Efficient 3D cell systems for neuronal induction are needed for future use in tissue regeneration. In this study, we have characterized the ability of neural stem/progenitor cells (NS/PC) to survive, proliferate, and differentiate in a collagen type I-hyaluronan scaffold. Embryonic, postnatal, and adult NS/PC were seeded in the present 3D scaffold and cultured in medium containing epidermal growth factor and fibroblast growth factor-2, a condition that stimulates NS/PC proliferation. Progenitor cells from the embryonic brain had the highest proliferation rate, and adult cells the lowest, indicating a difference in mitogenic responsiveness. NS/PC from postnatal stages down-regulated nestin expression more rapidly than both embryonic and adult NS/PC, indicating a faster differentiation process. After 6 days of differentiation in the 3D scaffold, NS/PC from the postnatal brain had generated up to 70% neurons, compared with 14% in 2D. NS/PC from other ages gave rise to approximately the same proportion of neurons in 3D as in 2D (9-26% depending on the source for NS/PC). In the postnatal NS/PC cultures, the majority of III-tubulin-positive cells expressed glutamate, -aminobutyric acid, and synapsin I after 11 days of differentiation, indicating differentiation to mature neurons. Here we report that postnatal NS/PC survive, proliferate, and efficiently form synapsin I-positive neurons in a biocompatible hydrogel.

Keywords
3D cultures, neural stem/progenitor cells, hydrogel, scaffold, neurogenesis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-11683 (URN)10.1002/jnr.21358 (DOI)000248516700008 ()17520747 (PubMedID)
Available from: 2007-10-17 Created: 2007-10-17 Last updated: 2017-12-11Bibliographically approved
2. Central nervous system stem/progenitor cells form neurons and peripheral glia after transplantation to the dorsal root ganglion.
Open this publication in new window or tab >>Central nervous system stem/progenitor cells form neurons and peripheral glia after transplantation to the dorsal root ganglion.
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2006 (English)In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 17, no 6, p. 623-628Article in journal (Refereed) Published
Abstract [en]

We asked whether neural stem/progenitor cells from the cerebral cortex of E14.5 enhanced green fluorescent protein transgenic mice are able to survive grafting and differentiate in the adult rat dorsal root ganglion. Neurospheres were placed in lumbar dorsal root ganglion cavities after removal of the dorsal root ganglia. Alternatively, dissociated neurospheres were injected into intact dorsal root ganglia. Enhanced green fluorescent protein-positive cells in the dorsal root ganglion cavity were located in clusters and expressed beta-III-tubulin or glial fibrillary acidic protein after 1 month, whereas after 3 months, surviving grafted cells expressed only glial fibrillary acidic protein. In the intact adult DRG, transplanted neural stem/progenitor cells surrounded dorsal root ganglion cells and fibers, and expressed glial but not neuronal markers. These findings show that central nervous system stem/progenitor cells can survive and differentiate into neurons and peripheral glia after xenotransplantation to the adult dorsal root ganglion.

Keywords
Actins/genetics, animals, cell differentiation/physiology, cells, cultured, Cerebral Cortex/*cytology/embryology, embryo, ganglia, spinal/*cytology/transplantation, gene expression/physiology, green fluorescent, Proteins/genetics, immunohistochemistry/methods, intermediate filament proteins/metabolism, mice, mice, inbred C57BL, transgenic, nerve tissue proteins/metabolism, neuroglia/*physiology, neurons/*physiology, stem cell transplantation/methods, stem cells/*physiology, time factors, tubulin/metabolism, nerve regeneration, neural stem/progenitor cell, satellite cell, Schwann cell, sensory neuron, spinal cord
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-22831 (URN)000237529300013 ()16603923 (PubMedID)
Available from: 2007-03-01 Created: 2007-03-01 Last updated: 2017-12-07Bibliographically approved
3. Grafted neural progenitors migrate and form neurons after experimental traumatic brain injury
Open this publication in new window or tab >>Grafted neural progenitors migrate and form neurons after experimental traumatic brain injury
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2009 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 27, no 4, p. 323-334Article in journal (Refereed) Published
Abstract [en]

PURPOSE

Neural stem and progenitor cells (NSPC) generate neurons and glia, a feature that makes them attractive for cell replacement therapies. However, efforts to transplant neural progenitors in animal models of brain injury typically result in high cell mortality and poor neuronal differentiation.

METHODS

In an attempt to improve the outcome for grafted NSPC after controlled cortical impact we transplanted Enhanced Green Fluorescent Protein (EGFP)-positive NSPC into the contra lateral ventricle of mice one week after injury.

RESULTS

Grafted EGFP-NSPC readily migrated to the injured hemisphere where we analyzed the proportion of progenitors and differentiated progeny at different time points. Transplantation directly into the injured parenchyma, resulted in few brains with detectable EGFP-NSPC. On the contrary, in more than 90% of the mice that received a transplant into the lateral ventricle detectable EGFP-positive cells were found. The cells were integrated into the lateral ventricle wall of the un-injured hemisphere, throughout the corpus callosum, and in the cortical perilesional area. At one-week post transplantation, grafted cells that had migrated to the perilesion area mainly expressed markers of neural progenitors and neurons, while in the corpus callosum and the ventricular lining, grafted cells with a glial fate were more abundant. After 3 months, grafted cells in the perilesion area were less abundant whereas cells that had migrated to the walls of the third- and lateral- ventricle of the injured hemisphere were still detectable, suggesting that the injury site remained a hostile environment.

CONCLUSION

Transplantation to the lateral ventricle, presumably for being a neurogenic region, provides a favorable environment improving the outcome for grafted NSPC both in term of their appearance at the cortical site of injury, and their acquisition of neural markers.

Place, publisher, year, edition, pages
Amsterdam: IOS Press, 2009
Keywords
TBI, EGFP transgenic mice, transplantation, migration, regeneration, neural stem cells, CNS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-110090 (URN)10.3233/RNN-2009-0481 (DOI)000269629700007 ()19738325 (PubMedID)
Available from: 2009-11-03 Created: 2009-11-03 Last updated: 2017-12-12Bibliographically approved
4. Ibuprofen attenuates the inflammatory response and allows formation of migratory neuroblasts from grafted stem cells after traumatic brain injury
Open this publication in new window or tab >>Ibuprofen attenuates the inflammatory response and allows formation of migratory neuroblasts from grafted stem cells after traumatic brain injury
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2012 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 30, no 1, p. 9-19Article in journal (Refereed) Published
Abstract [en]

Purpose: There is hope for neural stem and progenitor cells (NSPC) to enhance regeneration when transplanted to the injured brain after traumatic brain injury (TBI). So far, the therapeutic effects of NSPC transplantation have been hampered mainly by the notable death of the transplanted cells. Neuroinflammation may lead to additional cell death after TBI and we hypothesized that survival of grafted NSPC could be enhanced by anti-inflammatory treatment.

Methods: Mice that were subjected to controlled cortical impact TBI and grafted with NSPC, were treated with the non-steroidal anti-inflammatory drug ibuprofen.

Results: Ibuprofen was found to down-regulate the TBI-induced inflammatory response. In addition, migrating neuroblasts from transplanted cells were observed near the contusion and in the ipsilateral hippocampus in ibuprofen-treated animals only, suggesting that the anti-inflammatory treatment had beneficial effects on graft survival and/or differentiation. However, Morris Water Maze performance or TBI-induced tissue loss was not influenced by ibuprofen treatment.

Conclusions: Our data suggests that anti-inflammatory strategies may be a complement to enhance the outcome for the cell transplants following TBI.

Keywords
Neural stem cell, regeneration, transplantation, controlled cortical impact, eGFP
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-110094 (URN)10.3233/RNN-2011-0606 (DOI)000300955300002 ()
Available from: 2009-11-03 Created: 2009-11-03 Last updated: 2017-12-12Bibliographically approved

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