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Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology. (Elena Kozlova)
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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.

Place, publisher, year, edition, pages
2015. Vol. 5, 10666
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-251488DOI: 10.1038/srep10666ISI: 000356063500001PubMedID: 26053681OAI: oai:DiVA.org:uu-251488DiVA: diva2:806351
Funder
Swedish Research Council, 5420, 20716
Available from: 2015-04-20 Created: 2015-04-20 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Reconnecting the CNS and PNS with Stem Cell Transplantation
Open this publication in new window or tab >>Reconnecting the CNS and PNS with Stem Cell Transplantation
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Severe injury may result in disconnection between the peripheral and central nervous system. Regeneration of the central portion of sensory neurons into the spinal cord is notoriously poor in adult mammals, with low regenerative drive and an unpermissive central environment, most likely resulting in persistent loss of sensory function. A variety of strategies have been addressedto augment regeneration, including application of growth promoting factors, counteraction of inhibitory molecules, and provision of growth permissive substrates. Stem cells have been investigated in these contexts, as well as for the possibility of providing new neurons to act as a relay between the periphery and spinal cord. Here we have investigated different sources of neural stem cells for their ability to form neurons and glia after transplantation to the periphery; to project axons into the spinal cord; and to assist regeneration of surviving sensory neurons. These have been performed at two locations: the "dorsal root ganglion cavity", and the transitional zone following dorsal root avulsion. Neurons and glia were generated form mouse boundary cap neural crest stem cells and embryonic stem cell derived ventral spinal cord progenitors, and in addition to this, regeneration of sensory fibers was observed after transplantation of human fetal spinal cord derived progenitors and human embryonic stem cell derived ventral spinal cord progenitors. Further, delivery of neurotrophic factor mimetics via mesoporous silica nanoparticles proved a valuable tool for stem cell survival and differentiation. While technological advances make in vivo differentiation a realistic goal, our findings indicate that so far assisting regeneration of host sensory fibers to reconnect with the spinal cord by transplantation of stem cells is a more reliable strategy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1105
Keyword
stem cell transplantation, regenerative neurobiology, nerve injury repair
National Category
Neurosciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-251546 (URN)978-91-554-9252-6 (ISBN)
Public defence
2015-06-08, B/C2:301, BMC, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2015-05-18 Created: 2015-04-20 Last updated: 2015-07-07
2. Generation of functional neural progenitors for spinal cord transplantation
Open this publication in new window or tab >>Generation of functional neural progenitors for spinal cord transplantation
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
Regenerative Neurobiology, Stem cells, Sensory regeneration, Spinal cord injury
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-264580 (URN)
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
3. 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. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1365
Keyword
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: 2017-10-17

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