| 1. |
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| 2. |
- Aldskogius, Håkan, et al.
(författare)
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Central neuron-glial and glial-glial interactions following axon injury
- 1998
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Ingår i: Progress in Neurobiology. - 0301-0082 .- 1873-5118. ; 55:1, s. 1-26
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Tidskriftsartikel (refereegranskat)abstract
- Axon injury rapidly activates microglial and astroglial cells close to the axotomized neurons. Following motor axon injury, astrocytes upregulate within hour(s) the gap junction protein connexin-43, and within one day glial fibrillary acidic protein (GFAP). Concomitantly, microglial cells proliferate and migrate towards the axotomized neuron perikarya. Analogous responses occur in central termination territories of peripherally injured sensory ganglion cells. The activated microglia express a number of inflammatory and immune mediators. When neuron degeneration occurs, microglia act as phagocytes. This is uncommon after peripheral nerve injury in the adult mammal, however, and the functional implications of the glial cell responses in this situation are unclear. When central axons are injured, the glial cell responses around the affected neuron perikarya appears to be minimal or absent, unless neuron degeneration occurs. Microglia proliferate, and astrocytes upregulate GFAP along central axons undergoing anterograde, Wallerian, degeneration. Although microglia develop into phagocytes, they eliminate the disintegrating myelin very slowly, presumably because they fail to release molecules which facilitate phagocytosis. During later stages of Wallerian degeneration, oligodendrocytes express clusterin, a glycoprotein implicated in several conditions of cell degeneration. A hypothetical scheme for glial cell activation following axon injury is discussed, implying the injured neurons initially interact with adjacent astrocytes. Subsequently, neighbouring resting microglia are activated. These glial reactions are amplified by paracrine and autocrine mechanisms, in which cytokines appear to be important mediators. The specific functional properties of the activated glial cells will determine their influence on neuronal survival, axon regeneration, and synaptic plasticity. The control of the induction and progression of these responses are therefore likely to be critical for the outcome of, for example, neurotrauma, brain ischemia and chronic neurodegenerative diseases.
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| 3. |
- Aldskogius, Håkan, 1943-, et al.
(författare)
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Dorsal Root Injury : A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury
- 2021
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 10:9
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Forskningsöversikt (refereegranskat)abstract
- Unraveling the cellular and molecular mechanisms of spinal cord injury is fundamental for our possibility to develop successful therapeutic approaches. These approaches need to address the issues of the emergence of a non-permissive environment for axonal growth in the spinal cord, in combination with a failure of injured neurons to mount an effective regeneration program. Experimental in vivo models are of critical importance for exploring the potential clinical relevance of mechanistic findings and therapeutic innovations. However, the highly complex organization of the spinal cord, comprising multiple types of neurons, which form local neural networks, as well as short and long-ranging ascending or descending pathways, complicates detailed dissection of mechanistic processes, as well as identification/verification of therapeutic targets. Inducing different types of dorsal root injury at specific proximo-distal locations provide opportunities to distinguish key components underlying spinal cord regeneration failure. Crushing or cutting the dorsal root allows detailed analysis of the regeneration program of the sensory neurons, as well as of the glial response at the dorsal root-spinal cord interface without direct trauma to the spinal cord. At the same time, a lesion at this interface creates a localized injury of the spinal cord itself, but with an initial neuronal injury affecting only the axons of dorsal root ganglion neurons, and still a glial cell response closely resembling the one seen after direct spinal cord injury. In this review, we provide examples of previous research on dorsal root injury models and how these models can help future exploration of mechanisms and potential therapies for spinal cord injury repair.
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| 4. |
- Aldskogius, Håkan, et al.
(författare)
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Microglia and Neuropathic Pain
- 2013
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Ingår i: CNS & Neurological Disorders. - : Wiley. - 1871-5273 .- 1996-3181. ; 12:6, s. 768-772
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Tidskriftsartikel (refereegranskat)abstract
- Neuropathic pain is a serious consequence of injury or disease in the nervous system itself. Current treatment options for this condition are often unsatisfactory. From being originally viewed as a diseased caused by neuronal dysfunction, a growing body of evidence implicate activated microglia as a key player in the development of this pain condition. In this review, some of the evidence for this proposal is briefly discussed and placed in a translational context, pointing out the difficulties in translating commonly used animal models of neuropathic pain to the clinical condition, as well as emphasizing the broader role of activated microglia in the injured or diseased nervous system.
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| 5. |
- Aldskogius, Håkan, et al.
(författare)
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Strategies for repair of the deafferented spinal cord
- 2002
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Ingår i: Brain Research Reviews. - 0165-0173 .- 1872-6321. ; 40:1-3, s. 301-308
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Tidskriftsartikel (refereegranskat)abstract
- Deafferentation of the spinal cord by interruption of the sensory fibers in the dorsal roots highlights the problem of regeneration failure in the central nervous system. The injured dorsal root axons regenerate steadily, albeit slowly, in the peripheral compartment of the dorsal root, but abruptly cease to elongate when confronted with the interface between the peripheral and central nervous system, the dorsal root transitional zone (DRTZ). The glial cells of the CNS and their products together form this regeneration barrier. Recent years have witnessed several successful approaches to, at least in part, overcome this barrier. Particularly promising results have been obtained by (1). the replacement of adult non-regenerating dorsal root ganglion neurons with corresponding cells from embryonic or fetal donors, (2). the implantation of olfactory ensheathing cells at the DRTZ, and (3). immediate intrathecal infusion of growth factors to which dorsal root ganglion cells respond. In all these instances, growth of sensory axons into the adult spinal cord, as well as return of spinal cord connectivity, have been demonstrated. These findings suggest routes towards treatment strategies for plexus avulsion, and contribute to our understanding of possibilities to overcome regeneration failure in the spinal cord.
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| 6. |
- Brännvall, Karin, et al.
(författare)
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Central nervous system stem/progenitor cells form neurons and peripheral glia after transplantation to the dorsal root ganglion.
- 2006
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Ingår i: NeuroReport. - 0959-4965 .- 1473-558X. ; 17:6, s. 623-628
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Tidskriftsartikel (refereegranskat)abstract
- We asked whether neural stem/progenitor cells from the cerebral cortex of E14.5 enhanced green fluorescent protein transgenic mice are able to survive grafting and differentiate in the adult rat dorsal root ganglion. Neurospheres were placed in lumbar dorsal root ganglion cavities after removal of the dorsal root ganglia. Alternatively, dissociated neurospheres were injected into intact dorsal root ganglia. Enhanced green fluorescent protein-positive cells in the dorsal root ganglion cavity were located in clusters and expressed beta-III-tubulin or glial fibrillary acidic protein after 1 month, whereas after 3 months, surviving grafted cells expressed only glial fibrillary acidic protein. In the intact adult DRG, transplanted neural stem/progenitor cells surrounded dorsal root ganglion cells and fibers, and expressed glial but not neuronal markers. These findings show that central nervous system stem/progenitor cells can survive and differentiate into neurons and peripheral glia after xenotransplantation to the adult dorsal root ganglion.
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| 7. |
- Garcia-Bennett, Alfonso E., et al.
(författare)
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Delivery of Differentiation Factors by Mesoporous Silica Particles Assists Advanced Differentiation of Transplanted Murine Embryonic Stem Cells
- 2013
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Ingår i: Stem Cells Translational Medicine. - : Oxford University Press (OUP). - 2157-6564 .- 2157-6580. ; 2:11, s. 906-915
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Garcia-Bennett, Alfonso E., et al.
(författare)
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In vitro generation of motor neuron precursors from mouse embryonic stem cells using mesoporous nanoparticles
- 2014
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Ingår i: Nanomedicine. - 1743-5889 .- 1748-6963. ; 9:16, s. 2457-2466
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Stem cell-derived motor neurons (MNs) are utilized to develop replacement strategies for spinal cord disorders. Differentiation of embryonic stem cells into MN precursors involves factors and their repeated administration. We investigated if delivery of factors loaded into mesoporous nanoparticles could be effective for stem cell differentiation in vitro. Materials & methods: We used a mouse embryonic stem cell line expressing green fluorescent protein under the promoter for the MN-specific gene Hb9 to visualize the level of MN differentiation. The differentiation of stem cells was evaluated by expression of MN-specific transcription factors monitored by quantitative real-time PCR reactions and immunocytochemistry. Results: Mesoporous nanoparticles have strong affiliation to the embryoid bodies, penetrate inside the embryoid bodies and come in contact with differentiating cells. Conclusion: Repeated administration of soluble factors into a culture medium can be avoided due to a sustained release effect using mesoporous silica.
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| 9. |
- Goursaud, Stephanie, et al.
(författare)
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Cultured astrocytes derived from corpus callosum or cortical grey matter show distinct glutamate handling properties
- 2009
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 108:6, s. 1442-1452
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Tidskriftsartikel (refereegranskat)abstract
- While the astrocytic control of extracellular glutamate concentration at synaptic contacts is well characterized, little is known regarding the clearance of glutamate along axon tracts, even though local excitotoxic damage has been reported. Therefore, we have compared glutamate handling in astrocyte cultures derived from white matter (corpus callosum) and grey matter tissues (cortical structures). These populations of astrocytes showed clearly distinct phenotypes, adopting stellate or protoplasmic morphologies respectively. In addition, white matter astrocytes showed high densities of the intermediate filament proteins glial fibrillary acidic protein, vimentin and nestin. The glutamate-aspartate transporter and glutamate transporter-1, as well as glutamine synthetase, were found to be expressed at higher levels in white matter compared with grey matter astrocytes. Consistent with this aspartate uptake capacity was three to fourfold higher in white matter cells, and the use of specific inhibitors revealed a substantial activity of glutamate transporter-1, contrasting with grey matter cells where this transporter appeared poorly functional. In addition, expression of type 5 metabotropic glutamate receptors was considerably higher in white matter astrocytes where the agonist (S)-3,5-dihydroxyphenylglycine triggered a large release of intracellular calcium. Differences in these astrocyte cultures were also observed when exposed to experimental conditions that trigger glial activation. This study highlights typical features of cultured astrocytes derived from white matter tissues, which appear constitutively adapted to handle excitotoxic insults. Moreover, the expression and activity of the astroglial components involved in the control of glutamatergic transmission are reinforced when these cells are maintained under conditions mimicking a gliotic environment.
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| 10. |
- Grouwels, G., et al.
(författare)
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Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells
- 2012
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 55:7, s. 2016-2025
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesisEfficient stimulation of cycling activity in cultured beta cells would allow the design of new strategies for cell therapy in diabetes. Neural crest stem cells (NCSCs) play a role in beta cell development and maturation and increase the beta cell number in co-transplants. The mechanism behind NCSC-induced beta cell proliferation and the functional capacity of the new beta cells is not known.MethodsWe developed a new in vitro co-culture system that enables the dissection of the elements that control the cellular interactions that lead to NCSC-dependent increase in islet beta cells.ResultsMouse NCSCs were cultured in vitro, first in medium that stimulated their proliferation, then under conditions that supported their differentiation. When mouse islet cells were cultured together with the NCSCs, more than 35% of the beta cells showed cycle activity. This labelling index is more than tenfold higher than control islets cultured without NCSCs. Beta cells that proliferated under these culture conditions were fully glucose responsive in terms of insulin secretion. NCSCs also induced beta cell proliferation in islets isolated from 1-year-old mice, but not in dissociated islet cells isolated from human donor pancreas tissue. To stimulate beta cell proliferation, NCSCs need to be in intimate contact with the beta cells.Conclusions/interpretationCulture of islet cells in contact with NCSCs induces highly efficient beta cell proliferation. The reported culture system is an excellent platform for further dissection of the minimal set of factors needed to drive this process and explore its potential for translation to diabetes therapy.
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| 11. |
- Han, Yilin, et al.
(författare)
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Effects of microgravity on neural crest stem cells
- 2024
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to microgravity (μg) results in a range of systemic changes in the organism, but may also have beneficial cellular effects. In a previous study we detected increased proliferation capacity and upregulation of genes related to proliferation and survival in boundary cap neural crest stem cells (BC) after MASER14 sounding rocket flight compared to ground-based controls. However, whether these changes were due to μg or hypergravity was not clarified. In the current MASER15 experiment BCs were exposed simultaneously to μg and 1 g conditions provided by an onboard centrifuge. BCs exposed to μg displayed a markedly increased proliferation capacity compared to 1 g on board controls, and genetic analysis of BCs harvested 5 h after flight revealed an upregulation, specifically in μg-exposed BCs, of Zfp462 transcription factor, a key regulator of cell pluripotency and neuronal fate. This was associated with alterations in exosome microRNA content between μg and 1 g exposed MASER15 specimens. Since the specimens from MASER14 were obtained for analysis with 1 week’s delay, we examined whether gene expression and exosome content were different compared to the current MASER15 experiments, in which specimens were harvested 5 h after flight. The overall pattern of gene expression was different and Zfp462 expression was down-regulated in MASER14 BC μg compared to directly harvested specimens (MASER15). MicroRNA exosome content was markedly altered in medium harvested with delay compared to directly collected samples. In conclusion, our analysis indicates that even short exposure to μg alters gene expression, leading to increased BC capacity for proliferation and survival, lasting for a long time after μg exposure. With delayed harvest of specimens, a situation which may occur due to special post-flight circumstances, the exosome microRNA content is modified compared to fast specimen harvest, and the direct effects from μg exposure may be partially attenuated, whereas other effects can last for a long time after return to ground conditions.
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| 12. |
- Han, Yilin, et al.
(författare)
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Molecular genetic analysis of neural stem cells after space flight and simulated microgravity on earth
- 2021
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Ingår i: Biotechnology and Bioengineering. - : John Wiley & Sons. - 0006-3592 .- 1097-0290. ; 118:10, s. 3832-3846
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Tidskriftsartikel (refereegranskat)abstract
- Understanding how stem cells adapt to space flight conditions is fundamental for human space missions and extraterrestrial settlement. We analyzed gene expression in boundary cap neural crest stem cells (BCs), which are attractive for regenerative medicine by their ability to promote proliferation and survival of cocultured and co-implanted cells. BCs were launched to space (space exposed cells) (SEC), onboard sounding rocket MASER 14 as free-floating neurospheres or in a bioprinted scaffold. For comparison, BCs were placed in a random positioning machine (RPM) to simulate microgravity on earth (RPM cells) or were cultured under control conditions in the laboratory. Using next-generation RNA sequencing and data post-processing, we discovered that SEC upregulated genes related to proliferation and survival, whereas RPM cells upregulated genes associated with differentiation and inflammation. Thus, (i) space flight provides unique conditions with distinctly different effects on the properties of BC compared to earth controls, and (ii) the space flight exposure induces postflight properties that reinforce the utility of BC for regenerative medicine and tissue engineering.
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| 13. |
- Hanna-Mitchell, Ann T, et al.
(författare)
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The impact of neurotrophin-3 on the dorsal root transitional zone following injury
- 2008
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Ingår i: Spinal Cord. - 1362-4393 .- 1476-5624. ; 46:12, s. 804-810
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Tidskriftsartikel (refereegranskat)abstract
- Study design: Morphological and Stereological assessment of the dorsal root transitional zone (DRTZ) following complete crush injury, using light microscopy (LM) and transmission electron microscopy (TEM).Objectives: To assess the effect of exogenous neurotrophin-3 (NT-3) on the response of glial cells and axons to dorsal root damage.Setting: Department of Anatomy, University College Cork, Ireland and Department of Physiology, UMDS, University of London, UK.Methods: Cervical roots (C6-8) from rats which had undergone dorsal root crush axotomy 1 week earlier, in the presence (n = 3) and absence (n = 3) of NT-3, were processed for LM and TEM.Results: Unmyelinated axon number and size was greater in the DRTZ proximal ( Central Nervous System; CNS) and distal ( Peripheral Nervous System; PNS) compartments of NT-3-treated tissue. NT-3 was associated with a reduced astrocytic response, an increase in the proportion of oligodendrocytic tissue and a possible inhibition or delay of microglial activation. Disrupted-myelin volume in the DRTZ PNS and CNS compartments of treated tissue was lower, than in control tissue. In the PNS compartment, NT-3 treatment increased phagocyte and blood vessel numbers. It decreased myelinating activity, as sheath thickness was significantly lower and may also account for the noted lower Schwann cell and organelle volume in the test group.Conclusions: Our observations suggest that NT-3 interacts with non-neuronal tissue to facilitate the regenerative effort of damaged axons. This may be as a consequence of a direct action or indirectly mediated by modulation of non-neuronal responses to injury.
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| 14. |
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| 15. |
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| 16. |
- Hoeber, Jan, et al.
(författare)
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Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 17. |
- Kanaykina, Nadya, et al.
(författare)
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In vitro and in vivo effects on neural crest stem celldifferentiation by conditional activation of Runx1 short isoform and its effecton neuropathic pain behavior
- 2010
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 115:1, s. 56-64
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Runx1, a Runt domain transcription factor, controls thedifferentiation of nociceptors that express the neurotrophin receptor Ret,regulates the expression of many ion channels and receptors, and controls thelamina-specific innervation pattern of nociceptive afferents in the spinal cord. Moreover, mice lacking Runx1 exhibit specific defects in thermal and neuropathic pain. We investigated whether conditional activation of Runx1 short isoform(Runx1a), which lacks a transcription activation domain, influencesdifferentiation of neural crest stem cells (NCSCs) in vitro and in vivo duringdevelopment and whether postnatal Runx1a activation affects the sensitivity toneuropathic pain. METHODS: We activated ectopic expression of Runx1a in cultured NCSCs using the Tet-ON gene regulatory system during the formation ofneurospheres and analyzed the proportion of neurons and glial cells originatingfrom NCSCs. In in vivo experiments we applied doxycycline (DOX) to pregnant mice (days 8-11), i.e. when NCSCs actively migrate, and examined the phenotype ofoffsprings. We also examined whether DOX-induced activation of Runx1a in adultmice affects their sensitivity to mechanical stimulation following a constrictioninjury of the sciatic nerve. RESULTS: Ectopic Runx1a expression in cultured NCSCsresulted in predominantly glial differentiation. Offsprings in which Runx1a hadbeen activated showed retarded growth and displayed megacolon, pigment defects,and dystrophic dorsal root ganglia. In the neuropathic pain model, the threshold for mechanical sensitivity was markedly increased following activation of Runx1a.CONCLUSION: These data suggest that Runx1a has a specific role in NCSCdevelopment and that modulation of Runx1a activity may reduce mechanicalhypersensitivity associated with neuropathic pain.
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| 18. |
- Kosykh, Anastasiia, et al.
(författare)
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Neural crest stem cells from hair follicles and boundary cap have different effects on pancreatic islets in vitro
- 2015
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Ingår i: International Journal of Neuroscience. - London : Informa Healthcare. - 0020-7454 .- 1563-5279 .- 1543-5245. ; 125:7, s. 547-554
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Neural crest stem cells derived from the boundary cap (bNCSCs), markedly promote survival, proliferation and function of insulin producing β-cells in vitro and in vivo after coculture/transplantation with pancreatic islets [ 1, 2 ]. Recently, we have shown that beneficial effects on β-cells require cadherin contacts between bNCSCs and β-cells [ 3, 4 ]. Here we investigated whether hair follicle (HF) NCSCs, a potential source for human allogeneic transplantation, exert similar positive effects on β-cells.Materials and Methods:We established cocultures of HF-NCSCs or bNCSCs from mice expressing enhanced green fluorescent protein together with pancreatic islets from DxRed expressing mice or NMRI mice and compared their migration towards islet cells and effect on proliferation of β-cells as well as intracellular relations between NCSCs and islets using qRT-PCR analysis and immunohistochemistry.Results:Whereas both types of NCSCs migrated extensively in the presence of islets, only bNCSCs demonstrated directed migration toward islets, induced β-cell proliferation and increased the presence of cadherin at the junctions between bNCSCs and β-cells. Even in direct contact between β-cells and HF-NCSCs, no cadherin expression was detected.Conclusions:These observations indicate that HF-NCSCs do not confer the same positive effect on β-cells as demonstrated for bNCSCs. Furthermore, these data suggest that induction of cadherin expression by HF-NCSCs may be useful for their ability to support β-cells in coculture and after transplantation.
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| 19. |
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| 20. |
- Kozlova, Elena N., 1956-, et al.
(författare)
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Differentiation and migration of neural crest stem cells are stimulated by pancreatic islets
- 2009
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Ingår i: NeuroReport. - 0959-4965 .- 1473-558X. ; 20:9, s. 833-838
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Tidskriftsartikel (refereegranskat)abstract
- Neural crest stem cells (NCSCs) migrate during embryonic development towards the endoderm-derived pancreas and the interaction between NCSCs and beta-cellprogenitors is crucial for their mutual differentiation. In diabetes, loss ofbeta-cells or impaired beta-cell function is accompanied by nerve degeneration,which contributes to the progression of the disease. Here we show that adultpancreatic islets markedly promote differentiation of NCSCs towards neuronalphenotype in vitro and in vivo after transplantation and increase their migrationtowards islets. These findings indicate that pancreatic islets can be used topromote differentiation of NCSCs towards neuronal phenotype and that thisin-vitro system may help elucidate interactions between NCSCs and healthy ordiseased beta-cells.
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| 21. |
- Kozlova, Elena N, et al.
(författare)
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Human dorsal root ganglion neurons from embryonic donors extend axons into the host rat spinal cord along laminin-rich peripheral surroundings of the dorsal root transitional zone
- 1997
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Ingår i: Journal of Neurocytology. - 0300-4864 .- 1573-7381. ; 26:12, s. 811-822
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Tidskriftsartikel (refereegranskat)abstract
- Following dorsal root crush, the lesioned axons regenerate in the peripheral compartment of the dorsal root, but stop at the boundary between the peripheral and the central nervous system, the dorsal root transitional zone. We have previously shown that fibres from human fetal dorsal root ganglia grafted to adult rat hosts are able to grow into the spinal cord, but were not able to specify the route taken by the ingrowing fibres. In this study we have challenged the dorsal root transitional zone astrocyte boundary with human dorsal root ganglion transplants from 5-8-week-old embryos. By tracing immunolabelled human fibres in serial sections, we found that fibres consistently grow around the dorsal root transitional zone astrocytes in laminin-rich peripheral surroundings, and extend into the host rat spinal cord along blood vessels, either into deep or superficial laminae of the dorsal horn, or into the dorsal funiculus. Human fibres that did not have access to blood vessels grew on the spinal cord surface. These findings indicate, that in spite of a substantial growth capacity by axons from human embryonic dorsal root ganglion cells as well as their tolerance to non-permissive factors in the mature mammalian CNS, these axons are still sensitive to the repellent effects of astrocytes of the mature dorsal root transitional zone. Furthermore, this axonal ingrowth is consistently associated with laminin-expressing structures until the axons reach the host spinal cord.
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| 22. |
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| 23. |
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| 24. |
- König, Niclas, et al.
(författare)
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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
- 2011
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Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 20:11, s. 1847-1857
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 25. |
- König, Niclas, 1986-, et al.
(författare)
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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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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 26. |
- Lau Börjesson, Joey, et al.
(författare)
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Surface Coating of Pancreatic Islets With Neural Crest Stem Cells Improves Engraftment and Function After Intraportal Transplantation
- 2015
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Ingår i: Cell Transplantation. - 0963-6897 .- 1555-3892. ; 24:11, s. 2263-2272
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Tidskriftsartikel (refereegranskat)abstract
- The present study aimed to develop techniques for surface coating of islets with neural crest stem cells (NCSCs) in order to enable cotransplantation to the clinically used liver site and then investigate engraftment and function intraportally of such bioengineered islets. Mouse islets were coated during incubation with enhanced green fluorescent protein (EGFP)-expressing mouse NCSCs and transplanted into the portal vein to cure diabetic mice. An intravenous glucose tolerance test was performed at 1 month posttransplantation. Islet grafts were retrieved and evaluated for vascular density, nerves, and glial cells. NCSCs expressed a vast number of key angiogenic and neurotrophic factors. Mice transplanted with NCSC-bioengineered islets responded better to the glucose load than recipient mice with control islets. NCSCs remained present in the vicinity or had often migrated into the NCSC-coated islets, and an improved islet graft reinnervation and revascularization was observed. Transplanted NCSCs differentiated into both glial and neural cells in the islet grafts. We conclude that bioengineering of islets with NCSCs for intraportal transplantation provides a possibility to improve islet engraftment and function. Pending successful establishment of protocols for expansion of NCSCs from, for example, human skin or bone marrow, this strategy may be applied to clinical islet transplantation.
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| 27. |
- Levinsson, Anders, et al.
(författare)
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Functional connections are established in the deafferented rat spinal cord by peripherally transplanted human embryonic sensory neurons
- 2000
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 12:10, s. 3589-3595
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Tidskriftsartikel (refereegranskat)abstract
- Functionally useful repair of the mature spinal cord following injury requires axon growth and the re-establishment of specific synaptic connections. We have shown previously that axons from peripherally grafted human embryonic dorsal root ganglion cells grow for long distances in adult host rat dorsal roots, traverse the interface between the peripheral and central nervous system, and enter the spinal cord to arborize in the dorsal horn. Here we show that these transplants mediate synaptic activity in the host spinal cord. Dorsal root ganglia from human embryonic donors were transplanted in place of native adult rat ganglia. Two to three months after transplantation the recipient rats were examined anatomically and physiologically. Human fibres labelled with a human-specific axon marker were distributed in superficial as well as deep laminae of the recipient rat spinal cord. About 36% of the grafted neurons were double labelled following injections of the fluorescent tracers MiniRuby into the sciatic and Fluoro-Gold into the lower lumbar spinal cord, indicating that some of the grafted neurons had grown processes into the spinal cord as well as towards the denervated peripheral targets. Electrophysiological recordings demonstrated that the transplanted human dorsal roots conducted impulses that evoked postsynaptic activity in dorsal horn neurons and polysynaptic reflexes in ipsilateral ventral roots. The time course of the synaptic activation indicated that the human fibres were non-myelinated or thinly myelinated. Our findings show that growing human sensory nerve fibres which enter the adult deafferentated rat spinal cord become anatomically and physiologically integrated into functional spinal circuits.
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| 28. |
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| 29. |
- Ngamjariyawat, Anongnad, et al.
(författare)
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Co-Culture of Neural Crest Stem Cells (NCSC) and Insulin Producing Beta-TC6 Cells Results in Cadherin Junctions and Protection against Cytokine-Induced Beta-Cell Death
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4, s. e61828-
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Transplantation of pancreatic islets to Type 1 diabetes patients is hampered by inflammatory reactions at the transplantation site leading to dysfunction and death of insulin producing beta-cells. Recently we have shown that co-transplantation of neural crest stem cells (NCSCs) together with the islet cells improves transplantation outcome. The aim of the present investigation was to describe in vitro interactions between NCSCs and insulin producing beta-TC6 cells that may mediate protection against cytokine-induced beta-cell death.PROCEDURES: Beta-TC6 and NCSC cells were cultured either alone or together, and either with or without cell culture inserts. The cultures were then exposed to the pro-inflammatory cytokines IL-1β and IFN-γ for 48 hours followed by analysis of cell death rates (flow cytometry), nitrite production (Griess reagent), protein localization (immunofluorescence) and protein phosphorylation (flow cytometry).RESULTS: We observed that beta-TC6 cells co-cultured with NCSCs were protected against cytokine-induced cell death, but not when separated by cell culture inserts. This occurred in parallel with (i) augmented production of nitrite from beta-TC6 cells, indicating that increased cell survival allows a sustained production of nitric oxide; (ii) NCSC-derived laminin production; (iii) decreased phospho-FAK staining in beta-TC6 cell focal adhesions, and (iv) decreased beta-TC6 cell phosphorylation of ERK(T202/Y204), FAK(Y397) and FAK(Y576). Furthermore, co-culture also resulted in cadherin and beta-catenin accumulations at the NCSC/beta-TC6 cell junctions. Finally, the gap junction inhibitor carbenoxolone did not affect cytokine-induced beta-cell death during co-culture with NCSCs.CONCLUSION: In summary, direct contacts, but not soluble factors, promote improved beta-TC6 viability when co-cultured with NCSCs. We hypothesize that cadherin junctions between NCSC and beta-TC6 cells promote powerful signals that maintain beta-cell survival even though ERK and FAK signaling are suppressed. It may be that future strategies to improve islet transplantation outcome may benefit from attempts to increase beta-cell cadherin junctions to neighboring cells.
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| 30. |
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| 31. |
- Omelyanchik, Alexander, et al.
(författare)
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Boosting Magnetoelectric Effect in Polymer-Based Nanocomposites
- 2021
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Ingår i: Nanomaterials. - : MDPI. - 2079-4991. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Polymer-based magnetoelectric composite materials have attracted a lot of attention due to their high potential in various types of applications as magnetic field sensors, energy harvesting, and biomedical devices. Current researches are focused on the increase in the efficiency of magnetoelectric transformation. In this work, a new strategy of arrangement of clusters of magnetic nanoparticles by an external magnetic field in PVDF and PFVD-TrFE matrixes is proposed to increase the voltage coefficient (alpha ME) of the magnetoelectric effect. Another strategy is the use of 3-component composites through the inclusion of piezoelectric BaTiO3 particles. Developed strategies allow us to increase the alpha ME value from similar to 5 mV/cm.Oe for the composite of randomly distributed CoFe2O4 nanoparticles in PVDF matrix to similar to 18.5 mV/cm.Oe for a composite of magnetic particles in PVDF-TrFE matrix with 5%wt of piezoelectric particles. The applicability of such materials as bioactive surface is demonstrated on neural crest stem cell cultures.
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| 32. |
- Shteinfer-Kuzmine, Anna, et al.
(författare)
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A VDAC1-Derived N-Terminal Peptide Inhibits Mutant SOD1-VDAC1 Interactions and Toxicity in the SOD1 Model of ALS
- 2019
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Ingår i: Frontiers in Cellular Neuroscience. - : FRONTIERS MEDIA SA. - 1662-5102. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in superoxide dismutase (SOD1) are the second most common cause of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the death of motor neurons in the brain and spinal cord. SOD1 neurotoxicity has been attributed to aberrant accumulation of misfolded SOD1, which in its soluble form binds to intracellular organelles, such as mitochondria and ER, disrupting their functions. Here, we demonstrate that mutant SOD1 binds specifically to the N-terminal domain of the voltage-dependent anion channel (VDAC1), an outer mitochondrial membrane protein controlling cell energy, metabolic and survival pathways. Mutant SOD1(G93A) and SOD1(G85R), but not wild type SOD1, directly interact with VDAC1 and reduce its channel conductance. No such interaction with N-terminal-truncated VDAC1 occurs. Moreover, a VDAC1-derived N-terminal peptide inhibited mutant SOD1-induced toxicity. Incubation of motor neuron-like NSC-34 cells expressing mutant SOD1 or mouse embryonic stem cell-derived motor neurons with different VDAC1 N-terminal peptides resulted in enhanced cell survival. Taken together, our results establish a direct link between mutant SOD1 toxicity and the VDAC1 N-terminal domain and suggest that VDAC1 N-terminal peptides targeting mutant SOD1 provide potential new therapeutic strategies for ALS.
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| 33. |
- Takenaga, Keizo, et al.
(författare)
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Modified expression of Mts1/S100A4 protein in C6 glioma cells or surrounding astrocytes affects migration of tumor cells in vitro and in vivo
- 2007
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 25:3, s. 455-463
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Tidskriftsartikel (refereegranskat)abstract
- The calcium-binding Mtsl/S100A4 protein plays an important role in motility and metastatic activity of tumor cells. Recently we showed that Mts1/S100A4 is expressed in white matter astrocytes and influences their migration in vitro and in vivo. Here, we have investigated the role of Mts1/S100A4 expression in C6 glioma cells or surrounding astrocytes for migration ofC6 cells on astrocytes, using short interference (si) RNA to silence Mtsl/S100A4 expression. We find that in vitro, the migration of Mts1/S100A4 expressing and silenced C6 cells on astrocytes is predominantly dependent on the expression of Mts1/S100A4 in astrocytes, i.e. C6 cells preferably migrate on Mts1/S100A4-silenced astrocytes. In vivo, Mtsl/S100A4-positive C6 cells preferably migrate in white matter. In contrast Mts1/S100A4-silenced C6 cells avoid white matter and migrate in gray matter and meninges. Thus, the migration pattern ofC6 cells is affected by their intrinsic Mtsl/S100A4 expression as well as Mtsl/S100A4 expression in astrocytes. To investigate if Mts1/S100A4 has a significant role on brain tumor progression, we made quantitative RT-PCR analysis for the expression of S100A4/Mtsl in various grades of astrocytic tumors. Our data showed that high-grade glioblastomas express higher amount of S100A4/Mtsl than low-grade astrocytic tumors.
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| 34. |
- Trolle, Carl, 1985-, et al.
(författare)
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Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar
- 2017
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Ingår i: Regenerative Medicine. - : Future Medicine Ltd. - 1746-0751 .- 1746-076X. ; 12:4, s. 339-351
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Tidskriftsartikel (refereegranskat)abstract
- AIM: During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury.MATERIALS & METHODS: Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing.RESULTS: hNPs and bNCSCs form similar gaps in the glial scar, but unlike hNPs, bNCSCs contribute Mts1/S100A4 (calcium-binding protein) expression to the scar and do not assist sensory axon regeneration.CONCLUSION: bNCSC transplants contribute nonpermissive Mts1/S100A4-expressing cells to the glial scar after dorsal root avulsion.
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| 35. |
- Trolle, Carl, 1985-, et al.
(författare)
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Boundary cap neural crest stem cells promote angiogenesis after transplantation to avulsed dorsal roots in mice and induce migration of endothelial cells in 3D printed scaffolds
- 2024
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Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 826
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Tidskriftsartikel (refereegranskat)abstract
- Dorsal root avulsion injuries lead to loss of sensation and to reorganization of blood vessels (BVs) in the injured area. The inability of injured sensory axons to re-enter the spinal cord results in permanent loss of sensation, and often also leads to the development of neuropathic pain. Approaches that restore connection between peripheral sensory axons and their CNS targets are thus urgently need. Previous research has shown that sensory axons from peripherally grafted human sensory neurons are able to enter the spinal cord by growing along BVs which penetrate the CNS from the spinal cord surface. In this study we analysed the distribution of BVs after avulsion injury and how their pattern is affected by implantation at the injury site of boundary cap neural crest stem cells (bNCSCs), a transient cluster of cells, which are located at the boundary between the spinal cord and peripheral nervous system and assist the growth of sensory axons from periphery into the spinal cord during development. The superficial dorsal spinal cord vasculature was examined using intravital microscopy and intravascular BV labelling. bNCSC transplantation increased vascular volume in a non-dose responsive manner, whereas dorsal root avulsion alone did not decrease the vascular volume. To determine whether bNCSC are endowed with angiogenic properties we prepared 3D printed scaffolds, containing bNCSCs together with rings prepared from mouse aorta. We show that bNCSC do induce migration and assembly of endothelial cells in this system. These findings suggest that bNCSC transplant can promote vascularization in vivo and contribute to BV formation in 3D printed scaffolds.
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| 36. |
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| 37. |
- Åkesson, Elisabet, et al.
(författare)
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Long-term survival, robust neuronal differentiation, and extensive migration of human forebrain stem/progenitor cells transplanted to the adult rat dorsal root ganglion cavity
- 2008
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Ingår i: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 17:10-11, s. 1115-1123
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Tidskriftsartikel (refereegranskat)abstract
- Neurons in dorsal root ganglia (DRGs) transmit sensory information from peripheral tissues to the spinal cord. This pathway can be interrupted, for example, as the result of physical violence, traffic accidents, or complications during child delivery. As a consequence, the patient permanently loses sensation and often develops intractable neuropathic pain in the denervated area. Here we investigate whether human neural stem/progenitor cells (hNSPCs) transplanted to the DRG cavity can serve as a source for repairing lost peripheral sensory connections. We found that hNSPCs robustly differentiate to neurons, which survive long-term transplantation. The neuronal population in the transplants was tightly surrounded by astrocytes, suggesting their active role in neuron survival. Furthermore, 3 months after grafting hNSPCs were found in the dorsal root transitional zone (DRTZ) and within the spinal cord. The level of differentiation of transplanted cells was high in the core of the transplants whereas cells that migrated to the DRTZ and spinal cord were undifferentiated, nestin-expressing precursors. These data indicate that peripherally transplanted hNPSCs can be used for repair of dorsal root avulsion or spinal cord injuries; however, additional factors are required to guide their differentiation to the desired type of neurons. Furthermore, hNPSCs that migrate from the DRG cavity graft site to the DRTZ and spinal cord may provide trophic support for regenerating dorsal root axons, thereby allowing them to reenter the host spinal cord.
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