uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Generation of functional neural progenitors for spinal cord transplantation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Regenerative Neurobiology)ORCID iD: 0000-0001-5602-0850
2015 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Dorsal root avulsion injuries result in permanent impairment of sensory functions due to the disconnection of the peripheral nervous system from the spinal cord. Strategies aiming for the functional reconnection of sensory neurons with their targets in the spinal cord dorsal horn need to overcome the axonal growth non-permissive glial scar and provide a growth promoting environment. Stem cell therapy holds great promise in the context of root avulsion injuries as it combines the potential to provide a permissive and axonal growth attractive environment and the ability to form a neuronal relay between sensory neurons and spinal cord targets. In the first study, we show that human embryonic stem cell derived spinal cord neural progenitors(hNPs) restore sensorimotor functions in a model of dorsal root avulsion injury. The observed recovery of sensory functions was mediated by hNP cells forming growth permissive gates inthe glial scar that allowed spinal ingrowth of regenerating sensory axons. In the second study,we show that also human spinal cord neural stem/progenitor cells (hscNSPC) promote sensory axon ingrowth by the formation of a growth permissive tissue bridge that interferes with the spinal cord glial scar. Further, we tested whether this effect can be enhanced by combinatorial application of growth factors peptide mimetics. Interestingly, both hscNSPC and growth factor peptide mimetics alone but not in combination promote sensory regeneration. The observed failure of regeneration is likely caused by the reduced migration of hscNSPC when transplanted together with growth factor mimetics resulting in their inability to provide a continuous tissuebridge into the spinal cord. In the last study, we show first approaches to provide molecular tools that allow testing functional integration of stem cell derived neurons into the spinal cord.These tools are a prerequisite to test whether stem cells can also act as neuronal relays in the observed sensory regeneration events. In conclusion, this thesis provides first evidence that sensory regeneration is possible after dorsal root avulsion injury. This can be achieved by transplantation of human stem cell derived neuronal cells and to a certain degree by growth factor peptide mimetics.

Place, publisher, year, edition, pages
Uppsala: Uppsala University, Department of Neuroscience , 2015.
Keyword [en]
Regenerative Neurobiology, Stem cells, Sensory regeneration, Spinal cord injury
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-264580OAI: oai:DiVA.org:uu-264580DiVA: diva2:868067
Presentation
2015-12-14, B/C8:302, Husargatan 3, Uppsala, 10:15 (English)
Supervisors
Available from: 2015-11-18 Created: 2015-10-15 Last updated: 2016-02-16Bibliographically approved
List of papers
1. Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
Open this publication in new window or tab >>Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
Show others...
2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, 10666Article in journal (Refereed) Published
Abstract [en]

Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-251488 (URN)10.1038/srep10666 (DOI)000356063500001 ()26053681 (PubMedID)
Funder
Swedish Research Council, 5420, 20716
Available from: 2015-04-20 Created: 2015-04-20 Last updated: 2017-12-04Bibliographically approved
2. A Combinatorial Approach to Induce Sensory Regeneration after Dorsal Root Avulsion Injury
Open this publication in new window or tab >>A Combinatorial Approach to Induce Sensory Regeneration after Dorsal Root Avulsion Injury
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-265262 (URN)
Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2015-11-18
3. Genetically encoded recording of electrical activity and removal of tumorigenic cell populations of murine embryonic stem cell derived neurons
Open this publication in new window or tab >>Genetically encoded recording of electrical activity and removal of tumorigenic cell populations of murine embryonic stem cell derived neurons
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-265104 (URN)
Available from: 2015-10-22 Created: 2015-10-22 Last updated: 2015-11-18

Open Access in DiVA

No full text

Authority records BETA

Hoeber, Jan

Search in DiVA

By author/editor
Hoeber, Jan
By organisation
Department of Neuroscience
Neurosciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 1384 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf