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Reconnecting the CNS and PNS with Stem Cell Transplantation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Elena Kozlova, Regenerative Medicine)
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 [en]
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: urn:nbn:se:uu:diva-251546ISBN: 978-91-554-9252-6 (print)OAI: oai:DiVA.org:uu-251546DiVA: diva2:806430
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
List of papers
1. Forced Runx1 expression in human neural stem/progenitor cells transplanted to the rat dorsal root ganglion cavity results in extensive axonal growth specifically from spinal cord-derived neurospheres
Open this publication in new window or tab >>Forced Runx1 expression in human neural stem/progenitor cells transplanted to the rat dorsal root ganglion cavity results in extensive axonal growth specifically from spinal cord-derived neurospheres
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2011 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 20, no 11, 1847-1857 p.Article in journal (Refereed) Published
Abstract [en]

Cell replacement therapy holds great promise for treating a wide range of human disorders. However, ensuring the predictable differentiation of transplanted stem cells, eliminating their risk of tumor formation, and generating fully functional cells after transplantation remain major challenges in regenerative medicine. Here, we explore the potential of human neural stem/progenitor cells isolated from the embryonic forebrain (hfNSPCs) or the spinal cord (hscNSPCs) to differentiate to projection neurons when transplanted into the dorsal root ganglion cavity of adult recipient rats. To stimulate axonal growth, we transfected hfNSPC- and hscNSPC-derived neurospheres, prior to their transplantation, with a Tet-Off Runx1-overexpressing plasmid to maintain Runx1 expression in vivo after transplantation. Although pronounced cell differentiation was found in the Runx1-expressing transplants from both cell sources, we observed extensive, long-distance growth of axons exclusively from hscNSPC-derived transplants. These axons ultimately reached the dorsal root transitional zone, the boundary separating peripheral and central nervous systems. Our data show that hscNSPCs have the potential to differentiate to projection neurons with long-distance axonal outgrowth and that Runx1 overexpression is a useful approach to induce such outgrowth in specific sources of NSPCs.

National Category
Medical and Health Sciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-161344 (URN)10.1089/scd.2010.0555 (DOI)000296587400003 ()21322790 (PubMedID)
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2011-11-11 Created: 2011-11-11 Last updated: 2017-12-08
2. Delivery of Differentiation Factors by Mesoporous Silica Particles Assists Advanced Differentiation of Transplanted Murine Embryonic Stem Cells
Open this publication in new window or tab >>Delivery of Differentiation Factors by Mesoporous Silica Particles Assists Advanced Differentiation of Transplanted Murine Embryonic Stem Cells
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2013 (English)In: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 2, no 11, 906-915 p.Article in journal (Refereed) Published
Abstract [en]

Stem cell transplantation holds great hope for the replacement of damaged cells in the nervous system. However, poor long-term survival after transplantation and insufficiently robust differentiation of stem cells into specialized cell types in vivo remain major obstacles for clinical application. Here, we report the development of a novel technological approach for the local delivery of exogenous trophic factor mimetics to transplanted cells using specifically designed silica nanoporous particles. We demonstrated that delivering Cintrofin and Gliafin, established peptide mimetics of the ciliary neurotrophic factor and glial cell line-derived neurotrophic factor, respectively, with these particles enabled not only robust functional differentiation of motor neurons from transplanted embryonic stem cells but also their long-term survival in vivo. We propose that the delivery of growth factors by mesoporous nanoparticles is a potentially versatile and widely applicable strategy for efficient differentiation and functional integration of stem cell derivatives upon transplantation.

Keyword
Cell transplantation, Differentiation, Embryonic stem cells, Nervous system, Neural differentiation, Neural stem cell, Stem cell culture, Transplantation
National Category
Natural Sciences Engineering and Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-211443 (URN)10.5966/sctm.2013-0072 (DOI)000326312000017 ()
Note

De 3 första författarna delar förstaförfattarskapet

Available from: 2013-11-27 Created: 2013-11-25 Last updated: 2017-12-06Bibliographically approved
3. Murine neural crest stem cells and embryonic stem cell derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion
Open this publication in new window or tab >>Murine neural crest stem cells and embryonic stem cell derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion
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2017 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, no 1, 129-137 p.Article in journal (Refereed) Published
Abstract [en]

Spinal root avulsion results in paralysis and sensory loss, and is commonly associated with chronic pain. In addition to the failure of avulsed dorsal root axons to regenerate into the spinal cord, avulsion injury leads to extensive neuroinflammation and degeneration of second order neurons in the dorsal horn. The ultimate objective with the treatment of this condition is to counteract degeneration of spinal cord neurons and to achieve functionally useful regeneration/reconnection of sensory neurons with spinal cord neurons. Here we explore if stem cells transplanted on the surface of avulsed spinal cord can survive, differentiate and migrate into the damaged spinal cord during the first few weeks after this intervention. Murine boundary cap neural crest stem cells (bNCSCs) or embryonic stem cell (ESC)-derived, pre-differentiated neuron precursors were implanted acutely at the junction between avulsed dorsal roots L3-L6 and the spinal cord. Both types of cells survived transplantation, but showed distinctly different modes of differentiation. Thus, bNCSCs migrated into the spinal cord, expressed glial markers, and formed elongated tubes in the peripheral nervous system (PNS) compartment of the avulsed dorsal root transitional zone(DRTZ) area. In contrast, the ESC-transplants remained at the site of implantation and differentiated to motor neurons and interneurons. These data show that both stem cell types successfully survive implantation to the acutely injured spinal cord and maintained their differentiation and migration potential. These data suggest that depending on the source of neural stem cells, they can play different beneficial roles for recovery after dorsal root avulsion.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keyword
sensory neuron, spinal cord, dorsal root transitional zone, regeneration, migration, glial cells, Schwann cells, motor neurons
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-218684 (URN)10.1002/term.1893 (DOI)000394173600012 ()24753366 (PubMedID)
Funder
Swedish Research Council, 20716
Available from: 2014-02-14 Created: 2014-02-14 Last updated: 2017-12-06Bibliographically approved
4. Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents
Open this publication in new window or tab >>Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents
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2014 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, 60- p.Article in journal (Refereed) Published
Abstract [en]

The boundary cap is a transient group of neural crest-derived cells located at the presumptive dorsal root transitional zone (DRTZ) when sensory axons enter the spinal cord during development. Later, these cells migrate to dorsal root ganglia and differentiate into subtypes of sensory neurons and glia. After birth when the DRTZ is established, sensory axons are no longer able to enter the spinal cord. Here we explored the fate of mouse bNCSCs implanted to the uninjured DRTZ after dorsal root avulsion for their potential to assist sensory axon regeneration. Grafted cells showed extensive survival and differentiation after transplantation to the avulsed DRTZ. Transplanted cells located outside the spinal cord organized elongated tubes of Sox2/GFAP expressing cells closely associated with regenerating sensory axons or appeared as small clusters on the surface of the spinal cord. Others, migrating into the host spinal cordas single cells, differentiated to spinal cord neurons with different neurotransmitter characteristics, extensive fiber organization, and in some cases surrounded by glutamatergic terminal-like profiles. These findings demonstrate that bNCSCs implanted at the site of dorsal root avulsion injury display remarkable differentiation plasticity inside the spinal cord and in the peripheral compartment where they organize tubes associated with regenerating sensory fibers. These properties offer a basis for exploring the ability of bNCSCs to assist regeneration of sensory axons into the spinal cord and replace lost neurons in the injured spinal cord.

Place, publisher, year, edition, pages
BioMed Central, 2014
Keyword
neural stem cell, sensory neuron, spinal cord injury, cell differentiation, nerve regeneration, cell replacement
National Category
Neurosciences Neurology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-218685 (URN)10.1186/1471-2202-15-60 (DOI)000337318200001 ()
Funder
Swedish Research Council, 20716Swedish Research Council, 5420
Available from: 2014-02-14 Created: 2014-02-14 Last updated: 2017-12-06Bibliographically approved
5. 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
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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.

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
6. Human spinal cord neural progenitors alone but not in combination with growth factor mimetic loaded mesoporous silica assist regeneration of sensory fibers into the spinal cord after dorsal root avulsion
Open this publication in new window or tab >>Human spinal cord neural progenitors alone but not in combination with growth factor mimetic loaded mesoporous silica assist regeneration of sensory fibers into the spinal cord after dorsal root avulsion
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Spinal root avulsion injuries result in permanent loss of sensory function and often cause neuropathic pain. We recently showed that human embryonic stem cells derived neural progenitors (hNP) transplanted to the site of avulsed dorsal roots assist regeneration of sensory fibers into the adult mouse spinal cord. Here, we explored the potential of human spinal cord neural stem/progenitor cells (hscNSPCs) and of growth factor mimetics loaded nanoparticles to repair spinal root avulsion injury. We found that hscNSPCs and to some extent mimetic loaded nanoparticles support regeneration of sensory axons into the spinal cord when they are applied separately, whereas hscNSPCs implanted together with mimetic-loaded nanoparticles failed to support sensory  regeneration. These findings suggest that the positive effect of hscNSPCs may be eliminated by nanoparticle mediated release of neurotrophic factors due to changes in stem cell properties or surrounding cells at the place of avulsion, preventing growth of injured sensory axons into the spinal cord. Thus, hscNSPCs are able to assist restoration of sensory connections between the PNS and spinal cord, although not in combination with nanoparticle-delivered neurotrophic factor mimetics.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-251490 (URN)
Funder
Swedish Research Council, 20716
Available from: 2015-04-20 Created: 2015-04-20 Last updated: 2015-07-07

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