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Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Regenerative Neurobiology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.ORCID iD: 0000-0001-5602-0850
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
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2017 (English)In: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, ISSN 1878-7479, Vol. 14, no 3, p. 773-783Article in journal (Refereed) Published
Abstract [en]

ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1(G93A)) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1(G93A) MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1(G93A) MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1(G93A) MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models.

Place, publisher, year, edition, pages
2017. Vol. 14, no 3, p. 773-783
Keywords [en]
Amyotrophic lateral sclerosis, Neurodegeneration, Neuroglia, Oxidative stress, Transplantation
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-328588DOI: 10.1007/s13311-016-0505-8ISI: 000405725300022PubMedID: 28070746OAI: oai:DiVA.org:uu-328588DiVA, id: diva2:1136353
Funder
Swedish Research Council, 20716Stiftelsen Olle Engkvist ByggmästareAvailable from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-09-07Bibliographically approved
In thesis
1. Neural progenitors for sensory and motor repair
Open this publication in new window or tab >>Neural progenitors for sensory and motor repair
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Injury and neurodegenerative conditions of the spinal cord can lead to paralysis and loss of sensation. Cell therapeutic approaches can restore sensory innervation of the spinal cord following injury and protect spinal cord cells from degeneration. This thesis primarily focuses on the restoration of deaffarented sensory fibres following injury to the dorsal root and spinal cord. These injuries lead to the formation of a non-permissive glial scar that prevents sensory axons from reinnervating spinal cord targets. It takes advantage of a dorsal root injury model that closely mimics spinal root avulsion injuries occurring in humans. In the first part of the thesis, three different neural progenitor types from human or murine sources are tested for their regenerative properties following their transplantation to the site of dorsal root avulsion injury. In the second part, the ability of murine neural progenitors to protect spinal motor neurons from a neurodegenerative process is tested.

In the first original research article, I show that human embryonic stem cell derived neural progenitors are able to restore sensorimotor functions, mediated by the formation of a tissue bridge that allows ingrowth of sensory axons into the spinal cord. In the second research article, I present that murine boundary cap neural crest stem cells, a special type of neural progenitor that governs the entry of sensory axons into the spinal cord during development, are unable to form a permissive tissue bridge. This is possibly caused by the contribution of transplant derived ingrowth non-permissive glial cells. In the third research article, I show that human neural progenitors derived from foetal sources are capable of stimulating sensory ingrowth and that they ameliorate the glial scar. When this approach is combined with the delivery of sensory outgrowth stimulating neurotrophic factors, these cells fail to form a permissive tissue bridge and fail to modify the glial scar. In the final research article, murine boundary cap neural crest stem cells are shown to protect motor neurons, which harbor an amyotrophic lateral sclerosis causing mutation, from oxidative stress. Oxidative stress is a pathological component of amyotrophic lateral sclerosis in human patients.

Taken together, this thesis provides first evidence that sensory regeneration following a spinal root avulsion injury can be achieved by transplantation of human neural progenitors. In addition, it introduces murine boundary cap neural crest stem cells as interesting candidates for the cell therapeutic treatment of amyotrophic lateral sclerosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1365
Keywords
Regenerative Neurobiology, Stem cells, Sensory regeneration, Spinal cord injury, Amyotrophic Lateral Sclerosis, Neurodegeneration, Oxidative Stress
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-328590 (URN)978-91-513-0058-0 (ISBN)
Public defence
2017-10-23, B/C8:305, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2017-10-02 Created: 2017-08-31 Last updated: 2018-01-13

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Aggarwal, TanyaHoeber, JanIvert, PatrikVasylovska, SvitlanaKozlova, Elena

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