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Enhanced neuronal differentiation in a three-dimensional collagen-hyaluronan matrix
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2007 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 85, no 10, 2138-2146 p.Article 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.

Place, publisher, year, edition, pages
2007. Vol. 85, no 10, 2138-2146 p.
Keyword [en]
3D cultures, neural stem/progenitor cells, hydrogel, scaffold, neurogenesis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-11683DOI: 10.1002/jnr.21358ISI: 000248516700008PubMedID: 17520747OAI: oai:DiVA.org:uu-11683DiVA: diva2:39452
Available from: 2007-10-17 Created: 2007-10-17 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Neural Stem and Progenitor Cells as a Tool for Tissue Regeneration
Open this publication in new window or tab >>Neural Stem and Progenitor Cells as a Tool for Tissue Regeneration
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. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 500
Keyword
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:nbn:se:uu:diva-110095 (URN)978-91-554-7658-8 (ISBN)
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
2. Hyaluronan Derivatives and Injectable Gels for Tissue Engineering
Open this publication in new window or tab >>Hyaluronan Derivatives and Injectable Gels for Tissue Engineering
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The present work describes the preparation of hyaluronan derivatives and hydrogels with potential use in tissue engineering applications. A potentially injectable hydrogel consisting of hyaluronan and collagen was successfully used to grow neurons in vitro by encapsulation of neural stem and progenitor cells. Attempts were further made to establish a suitable modification strategy which could be used for the preparation of in vivo cross-linkable hyaluronan derivatives. The synthesis of a model substance consisting of a D-glucuronate derivative which could simplify the development of such a modification technique is described, although a new method to prepare hyaluronan derivatives was found without its use. The modification strategy involves the use of a triazine-reagent which enables the covalent attachment of hydrophilic and hydrophobic amines to hyaluronan carboxyl groups in a controlled fashion under mild conditions. Using triazine-activated amidation we synthesized an aldehyde-derivative of hyaluronan which was used to prepare gels by cross-linking with hydrazide-modified polyvinyl-alcohol. Gels were formed in less than 1 minute by mixing equal volumes of the polymer derivatives and they were subsequently used as a carrier for bone morphogenetic protein-2. An in vitro release study showed that approximately 88% of the growth factor is retained in the gel over a 4 week period. The ability to form new bone in vivo was further evaluated in an ectopic rat model by the injection of gels containing 30 µg BMP-2. Radiographic and histological examination 4 and 10 weeks after injection showed the formation of new bone without any signs of inflammation or foreign body response. Hydroxyapatite particles were further added to improve the mechanical properties of the gel, and a comparative study was conducted. This time the induced tissue consisted not only of bone, but also of interconnected cartilage and tendon, as confirmed by histology and immunohistochemistry.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2008. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 573
Keyword
Hyaluronan, Hydrogel, Tissue Engineering, Scaffold, Minimally invasive strategy, Bone morphogenetic protein, Hydroxyapatite, Bone, Cartilage, Tendon
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-9357 (URN)978-91-554-7335-8 (ISBN)
Public defence
2008-12-05, Polhemsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2010-03-04Bibliographically approved

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Bergman, KristofferBowden, TimHilborn, JönsForsberg-Nilsson, Karin

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