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  • 1.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Mechanisms and consequences of microglial responses to peripheral axotomy2011In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 3, p. 857-868Article in journal (Refereed)
    Abstract [en]

    Microglia respond rapidly to injury of peripheral nerve axons (axotomy). This response is integrated into the responses of the injured neurons, i.e. processes for neuron survival, axon regeneration and restoration of target contact. The microglial response is also integrated in changes in presynaptic terminals on axotomized motor or autonomic neurons and in changes in the central terminals of peripherally axotomized sensory neurons. Microglia also has an established role in interacting with astrocytes to shape their response to peripheral axotomy. Axotomy models in mice have demonstrated a role for microglia in regulating the entry of lymphocytes into motor nuclei or sensory areas following peripheral axotomy. Whether this is a universal component of peripheral nerve injury remains to be determined. Under certain circumstances, microglia activated by axotomy are major contributors to CNS pathology, e.g. in models of neuropathic pain. However, the general roles played by microglia after peripheral nerve injury are still incompletely understood. Early proposals that the microglial reaction to peripheral nerve injury is preparatory for the eventuality of neuron degeneration may still have relevance.

  • 2.
    Aldskogius, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Berens, Christian
    Kanaykina, Nadegda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Liakhovitskaia, Anna
    Medvinsky, Alexander
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Schreiner, Silke
    Wegner, Michael
    Hjerling-Leffler, Jens
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Regulation of boundary cap neural crest stem cell differentiation after transplantation2009In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 27, no 7, p. 1592-1603Article in journal (Refereed)
    Abstract [en]

    Success of cell replacement therapies for neurological disorders will dependlargely on the optimization of strategies to enhance viability and control thedevelopmental fate of stem cells after transplantation. Once transplanted,stem/progenitor cells display a tendency to maintain an undifferentiatedphenotype or differentiate into inappropriate cell types. Gain and loss offunction experiments have revealed key transcription factors which drivedifferentiation of immature stem/progenitor cells toward more mature stages andeventually to full differentiation. An attractive course of action to promotesurvival and direct the differentiation of transplanted stem cells to a specific cell type would therefore be to force expression of regulatory differentiationmolecules in already transplanted stem cells, using inducible gene expressionsystems which can be controlled from the outside. Here, we explore thishypothesis by employing a tetracycline gene regulating system (Tet-On) to drivethe differentiation of boundary cap neural crest stem cells (bNCSCs) toward asensory neuron fate after transplantation. We induced the expression of the keytranscription factor Runx1 in Sox10-expressing bNCSCs. Forced expression of Runx1strongly increased transplant survival in the enriched neurotrophic environmentof the dorsal root ganglion cavity, and was sufficient to guide differentiationof bNCSCs toward a nonpeptidergic nociceptive sensory neuron phenotype both invitro and in vivo after transplantation. These findings suggest that exogenousactivation of transcription factors expression after transplantation instem/progenitor cell grafts can be a constructive approach to control theirsurvival as well as their differentiation to the desired type of cell and thatthe Tet-system is a useful tool to achieve this.

  • 3.
    Aldskogius, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Microglia and Neuropathic Pain2013In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 12, no 6, p. 768-772Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Aldskogius, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Strategies for repair of the deafferented spinal cord2002In: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 40, no 1-3, p. 301-308Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Anderberg, Leif
    et al.
    Lunds universitet.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Holtz, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Spinal cord injury: scientific challenges for the unknown future2007In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 112, no 3, p. 259-288Article, review/survey (Other academic)
    Abstract [en]

    The history of spinal cord injuries starts with the ancient Egyptian medical papyrus known as the Edwin Smith Surgical Papyrus. The papyrus, written about 2500 B. C. by the physician and architect of the Sakkara pyramids Imhotep, describes "crushed vertebra in his neck" as well as symptoms of neurological deterioration. An ailment not to be treated was the massage to the patients at that time. This fatalistic attitude remained until the end of World War II when the first rehabilitation centre focused on the rehabilitation of spinal cord injured patients was opened. Our knowledge of the pathophysiological processes, both the primary as well as the secondary, has increased tremendously. However, all this knowledge has only led to improved medical care but not to any therapeutic method to restore, even partially, the neurological function. Neuroprotection is defined as measures to counteract secondary injury mechanisms and/or limit the extent of damage caused by self-destructive cellular and tissue processes. The co-existence of several distinctly different injury mechanisms after trauma has provided opportunities to explore a large number of potentially neuroprotective agents in animal experiments such as methylprednisolone sodium succinate. The results of this research have been very discouraging and pharmacological neuroprotection for patients with spinal cord injury has fallen short of the expectations created by the extensive research and promising observations in animal experiments. The focus of research has now, instead, been transformed to the field of neural regeneration. This field includes the discovery of regenerating obstacles in the nerve cell and/or environmental factors but also various regeneration strategies such as bridging the gap at the site of injury as well as transplantation of foetal tissue and stem cells. The purpose of this review is to highlight selected experimental and clinical studies that form the basis for undertaking future challenges in the research field of spinal cord injury. We will focus our discussion on methods either preventing the consequences of secondary injury in the acute period ( neuroprotection) and/or various techniques of neural regeneration in the sub-acute and chronic phase and finally expose some thoughts about future avenues within this scientific field.

  • 6.
    Friederich, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Johansson, Magnus
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 205-212Article in journal (Refereed)
    Abstract [en]

    Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.

  • 7.
    Garcia-Bennett, Alfonso E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Kozhevnikova, Mariya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    König, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Zhou, Chunfang
    Leao, Richardson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Knöpfel, Thomas
    Pankratova, Stanislava
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Berezin, Vladimir
    Bock, Elisabeth
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Delivery of Differentiation Factors by Mesoporous Silica Particles Assists Advanced Differentiation of Transplanted Murine Embryonic Stem Cells2013In: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 2, no 11, p. 906-915Article in journal (Refereed)
    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.

  • 8.
    Grapensparr, Liza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The therapeutic role of endothelial progenitor cells in Type 1 diabetes mellitus2011In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 6, no 5, p. 599-605Article, review/survey (Refereed)
    Abstract [en]

    Pancreatic beta-cells sense and adjust the blood glucose level by secretion of insulin. In Type 1 diabetes mellitus, these insulin-producing cells are destroyed, leaving the patients incapable of regulating blood glucose homeostasis. At the time of diagnosis, most patients still have 20-30% of their original beta-cell mass remaining. These residual beta-cells are targets for intervention therapies aimed at preventing further autoimmune destruction, in addition to increasing the number of existing beta-cells. Such a therapeutic option is highly desirable since it may lead to a full recovery of newly diagnosed patients, with no need for further treatment with immunosuppressant drugs or exogenous insulin administration. In this article, we propose that endothelial progenitor cells, a cell type known to promote and support neovascularization following endothelial injury, may be used as part of a combinational stem cell therapy aimed to improve the vascularization, survival and proliferation of beta-cells.

  • 9. Grouwels, G.
    et al.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Leuckx, G.
    Ngamjariyawat, Anongnad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Yuchi, Y.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Van de Casteele, M.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Heimberg, H.
    Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 7, p. 2016-2025Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis

    Efficient 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.

    Methods

    We 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.

    Results

    Mouse 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/interpretation

    Culture 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.

  • 10. Hanna-Mitchell, Ann T
    et al.
    O'Leary, David
    Mobarak, M
    Ramer, Matt S
    McMahon, Stephen B
    Priestley, John V
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Dockery, Peter
    Fraher, Joch P
    The impact of neurotrophin-3 on the dorsal root transitional zone following injury2008In: Spinal Cord, ISSN 1362-4393, E-ISSN 1476-5624, Vol. 46, no 12, p. 804-810Article in journal (Refereed)
    Abstract [en]

    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.

  • 11.
    Kanaykina, Nadya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Abelson, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    King, Dale
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Liakhovitskaia, Anna
    Schreiner, Silke
    Wegner, Michael
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    In vitro and in vivo effects on neural crest stem celldifferentiation by conditional activation of Runx1 short isoform and its effecton neuropathic pain behavior2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 1, p. 56-64Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Kozlova, Elena N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Differentiation and migration of neural crest stem cells are stimulated by pancreatic islets2009In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 20, no 9, p. 833-838Article in journal (Refereed)
    Abstract [en]

    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.

  • 13.
    Kozlova, Elena N
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Seiger, Åke
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    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 zone1997In: Journal of Neurocytology, ISSN 0300-4864, E-ISSN 1573-7381, Vol. 26, no 12, p. 811-822Article in journal (Refereed)
    Abstract [en]

    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.

  • 14. Kullberg, Susanna
    et al.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Ulfhake, Brun
    Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord2001In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 899, no 1-2, p. 169-186Article in journal (Refereed)
    Abstract [en]

    With advancing age, the incidence of neuronal atrophy and dystrophy increases and, in parallel, behavioural sensorimotor impairment becomes overt. Activated microglia has been implicated in cytotoxic and inflammatory processes in neurodegenerative diseases as well as during aging. Here we have used immunohistochemistry and in situ hybridization to examine the expression of OX42, ED1, ED2, GFAP and clusterin in CNS of young adult and behaviourally tested aged rats (30-month-old), to study the occurrence of activated microglia/ED1 positive macrophages in senescence and to what extent this correlates with astrogliosis and signs of sensorimotor impairment among the individuals. The results show a massive region-specific increase in activated microglia and ED1 expressing cell profiles in aged rats. The infiltration was most prominent in the spinal cord dorsal columns, including their sensory relay nuclei, and the outer portions of the lateral and ventral columns. At such sites the occurrence of macrophages coincided with increased levels of GFAP and positive correlations were evident between the labeling for, on the one hand, OX42 and, on the other, GFAP and ED1. Also, the ventral and dorsal roots were heavily infiltrated by ED1 positive cells. The signs of gliosis were most pronounced among aged rats with advanced sensorimotor impairment. In contrast, the grey matter of aged rats showed very few activated microglia/ED1 labeled cells despite signs of focal astrogliosis. ED2 expression was confined to perivascular cells and leptominges with a similar labeling pattern in young and aged rats. In aged rats increased expression of clusterin was observed in GFAP-immunoreactive profiles of the white matter only. It is suggested that this increase may reflect a response to degenerative/inflammatory processes.

  • 15.
    König, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kapuralin, Katarina
    University of Zagreb School of Medicine.
    Adameyko, Igor
    Karolinska Institutet.
    Mitrecic, Dinko
    University of Zagreb School of Medicine.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Shortland, Peter
    Queen Mary University of London.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Murine neural crest stem cells and embryonic stem cell derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion2017In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, no 1, p. 129-137Article in journal (Refereed)
    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.

  • 16.
    König, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Åkesson, Elisabet
    Telorack, Michèle
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Ngamjariyawat, Anongnad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Sundström, Erik
    Oster, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Berens, Christian
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Seiger, Åke
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    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 neurospheres2011In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 20, no 11, p. 1847-1857Article in journal (Refereed)
    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.

  • 17. Levinsson, Anders
    et al.
    Holmberg, Hans
    Schouenborg, Jens
    Seiger, Åke
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Functional connections are established in the deafferented rat spinal cord by peripherally transplanted human embryonic sensory neurons2000In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 12, no 10, p. 3589-3595Article in journal (Refereed)
    Abstract [en]

    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.

  • 18.
    Liu, Li
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Svensson, Mikael
    Ultrastructural localization of immunoglobulin G and complement C9 in the brain stem and spinal cord following peripheral nerve injury: an immunoelectron microscopic study1998In: Journal of Neurocytology, ISSN 0300-4864, E-ISSN 1573-7381, Vol. 27, no 10, p. 737-748Article in journal (Refereed)
    Abstract [en]

    The ultrastructural localization of immunoreactivity for immunoglobulin G (IgG), F(ab')2 and complement C9 was examined with preembedding immunoelectron microscopy in the hypoglossal nucleus and gracile nucleus as well as in the L4 spinal cord dorsal horn 1 week following hypoglossal or sciatic nerve transection, respectively. Only a few scattered immunoreactive profiles were observed on the unoperated side. On the operated side, IgG and F(ab')2 immunoreactivity was present in the membranes of all reactive microglial cells observed. In addition, the cell membrane of some hypoglossal motoneurons showed IgG immunoreactivity. Complement C9 immunoreactivity was present in the cytoplasm of all reactive microglial cells examined. In addition, there was diffuse C9 immunoreactivity in motoneuron perikarya ipsilateral to nerve injury as well as in cell membranes in the neuropil, some of which could be identified as neuronal. Our interpretation of these findings is (1) that peripheral nerve injury results in binding of IgG to reactive microglia, as well as to some axotomized neurons, and (2) that C9 is synthesized by reactive microglia in response to axon injury and is also associated with axotomized motoneurons. These findings suggest that IgG and complement C9 are involved in microglia-neuron interactions after peripheral nerve injury.

  • 19.
    Liu, Li
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Lioudyno, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tao, Ran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Eriksson, Petri
    Svensson, Mikael
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Hereditary absence of complement C5 in adult mice influences Wallerian degeneration, but not retrograde responses, following injury to peripheral nerve1999In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 4, no 2, p. 123-133Article in journal (Refereed)
    Abstract [en]

    We have examined the role of complement component 5 (C5) in peripheral nerve fiber degeneration and regeneration, as well as in glial and neuronal cell responses in the central nervous system (CNS). Adult congenic mice lacking C5 (C5(-)) and the corresponding normal strain (C5(+)) were used. Macrophage recruitment as well as axonal and myelin sheath elimination were delayed from 1 to 21 days postinjury in C5(-) mice compared to the C5(+) group after sciatic nerve crush. Despite this, recovery of motor function was not delayed. In the CNS, microglial cells and astrocytes responded in the same way from 3 to 21 days after sciatic nerve injury in C5(-) and C5(+) mice, and the extent of neuron death following hypoglossal nerve avulsion was the same in both groups. These findings suggest that C5 and/or its derivatives play an important role in initiating the recruitment of macrophages to the injured nerve and, probably indirectly, in early remyelination of regenerating axons, but does not influence the longterm functional restoration or axotomy-induced nerve cell death. C5-derived molecules do not appear to participate in central glial cell responses to peripheral nerve injury. These findings elucidate new aspects on the functional role of the complement system in the peripheral nervous system following peripheral nerve injury.

  • 20.
    Liu, Li
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Persson, Jonas
    Svensson, Mikael
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Glial Cell Responses, Complement and Clusterin in the Central Nervous System Following Dorsal Root Transection1998In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 23, no 3, p. 221-238Article in journal (Refereed)
    Abstract [en]

    We have examined the glial cell response, the possible expression of compounds associated with the complement cascade, including the putative complement inhibitor clusterin, and their cellular association during Wallerian degeneration in the central nervous system. Examination of the proliferation pattern revealed an overall greater mitotic activity after rhizotomy, an exclusive involvement of microglia in this proliferation after peripheral nerve injury, but, in addition, a small fraction of proliferating astrocytes after rhizotomy. Immunostaining with the phagocytic cell marker ED1 gradually became very prominent after rhizotomy, possibly reflecting a response to the extensive nerve fiber disintegration. Lumbar dorsal rhizotomy did not induce endogenous immunoglobulin G (IgG) deposition or complement expression in the spinal cord dorsal horn, dorsal funiculus, or gracile nucleus. This is in marked contrast to the situation after peripheral nerve injury, which appears to activate the entire complement cascade in the vicinity of the central sensory processes. Clusterin, a multifunctional protein with complement inhibitory effects, was markedly upregulated in the dorsal funiculus in astrocytes. In addition, there was an intense induction of clusterin expression in the degenerating white matter in oligodendrocytes, possibly reflecting a degeneration process in these cells. The findings suggest that 1) complement expression by microglial cells is intimately associated with IgG deposition; 2) axotomized neuronal perikarya, but not degenerating central fibers, undergo changes which induce such deposition; and 3) clusterin is not related to complement expression following neuronal injury but participates in regulating the state of oligodendrocytes during Wallerian degeneration.

  • 21.
    Liu, Li
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Svensson, Mikael
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Clusterin upregulation following rubrospinal tract lesion in the adult rat1999In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 157, no 1, p. 69-76Article in journal (Refereed)
    Abstract [en]

    We have examined the expression of the multifunctional protein clusterin in the axotomized red nucleus, at the lesion site in the lateral funiculus of C3, as well as along the Wallerian degeneration in the lateral funiculus of T1. There was a marked increase in clusterin-immunoreactivity (IR) and clusterin mRNA in red nucleus nerve cell bodies. An early, transient occurrence of large, heavily clusterin-IR globules were found in axons in the spinal cord at the lesion site in C3 as well as a marked upregulation of mRNA for clusterin, presumably associated with reactive astrocytes and oligodendrocytes from 1 to 4 weeks postoperatively. Clusterin-IR and its mRNA were markedly increased in the zone of Wallerian degeneration at T1, where some strongly expressing cells were identified as oligodendrocytes. Taken together with previous changes in clusterin expression following peripheral nerve and dorsal root injury, we suggest that this protein is involved in regenerative as well as degenerative neural responses.

  • 22. Mattsson, Per
    et al.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Svensson, Mikael
    Nimodipine-induced improved survival rate of facial motor neurons following intracranial transection of the facial nerve in the adult rat1999In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 90, no 4, p. 760-765Article in journal (Refereed)
    Abstract [en]

    OBJECT:

    Neuronal survival is an important factor in the achievement of functional restitution after peripheral nerve injuries. Intracranial tumors or trauma may cause patients to exhibit a temporary or permanent facial nerve palsy. Nimodipine, which acts as an antagonist to L-type voltage-gated calcium channels, has been shown to be neuroprotective in various lesion models of the central and peripheral nervous systems. The aim of the present study was to evaluate the effect of nimodipine on motor neuron survival in the facial motor nucleus following intracranial transection of the adult rat facial nerve.

    METHODS:

    The facial nerve was cut intracranially in the posterior cranial fossa. Nimodipine was administered orally preoperatively for 3 days and postoperatively for up to 1 month, after which the number of neuronal profiles was quantified. The glial reaction was studied in the facial nucleus for up to 1 month by using immunocytochemical analysis. There was a significantly larger proportion of surviving motor neurons 1 month postinjury in animals treated with nimodipine (61+/-6.7%) in comparison with untreated animals (26.8+/-11.3%). Immunocytochemical analysis showed an increase in the amount of OX42 (microglia), ED1 (macrophages), and anti-glial fibrillary acidic protein (astrocytes) ipsilateral to the nerve injury; however, there was no difference between the two experimental groups of animals 2 to 28 days after surgery.

    CONCLUSIONS:

    The authors propose a neuroprotective role for nimodipine, which may be useful as a "cranial nerve protective agent" following insults such as head injury or skull base surgery.

  • 23. Mattsson, Per
    et al.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Svensson, Mikael
    The novel pyrrolopyrimidine PNU-101033-E improves facial motor neuron survival following intracranial axotomy of the facial nerve in the adult rat1999In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 16, no 9, p. 793-803Article in journal (Refereed)
    Abstract [en]

    Neuronal survival is important to functional restitution following axotomy. Proximal lesions of the facial nerve, due to head trauma or tumor growth, for example, may cause long-standing or even permanent facial nerve palsy. Betamethasone has been used by several neurosurgical clinics for the treatment of postoperative facial nerve palsy; however, this practice is based only on clinical experience. The aim of the present study was to explore the putative effect on facial motor neuron survival of a novel lazaroid (pyrrolopyrimidine, PNU-101033-E) and furthermore to compare the effects with those of betamethasone, following intracranial transection of the facial nerve in adult rats. Both agents are known to inhibit lipid peroxidation by free radical scavenging. The lesion model used has recently been reported to induce massive neuronal cell death with a relative survival of 26.8 +/- 11.3% 1 month after lesion. Oral administration of lazaroids or daily injections of betamethasone followed surgery for 1 month, after which quantification of motor neuronal profiles was performed in the facial nucleus. Lazaroid-treated animals showed a significantly enhanced neuronal survival (68.0 +/- 9.8%), whereas no significant difference was found in betamethasone-treated animals (33.1 +/- 11.7%). The microglial and astrocytic responses in the facial nucleus were intense on the operated sides in betamethasone-treated as well as lazaroid-treated animals, and no differences in comparison with untreated animals were found. In conclusion, we found that the novel pyrrolopyrimidine PNU-101033-E, but not betamethasone, significantly enhanced nerve cell survival. This agent may therefore serve as a useful neuroprotective agent following intracranial trauma to the facial nerve and should be further evaluated for clinical use.

  • 24. Mattsson, Per
    et al.
    Jansson, Ann-Marie
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Svensson, Mikael
    Nimodipine promotes regeneration and functional recovery after intracranial facial nerve crush2001In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 347, no 1, p. 106-117Article in journal (Refereed)
    Abstract [en]

    The calcium flow inhibitor, nimodipine, has been shown to promote motor neuron survival in the facial nucleus after intracranial facial nerve transection. However, it has not been known whether the neuroprotective effects primarily involve survival of nerve cell bodies or outgrowth and/or myelination of nerve fibers. Here, we studied the effects of nimodipine in a different injury model in which the facial nerve was unilaterally crushed intracranially. This lesion caused complete anterograde degeneration and partial retrograde degeneration that were studied with a combination of several stereological methods. Nimodipine did not attenuate the modest lesion-induced neuronal loss (13%) but accelerated the time course of functional recovery and axonal regrowth, inducing increased numbers and sizes of myelinated axons in the facial nerve. It is interesting to note that nimodipine also enlarged the axons and the myelin sheaths in the nonlesioned facial nerve, which points to the possibility of using this substance for new clinical applications to promote axonal growth and remyelination.

  • 25.
    Ngamjariyawat, Anongnad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Turpaev, Kyril
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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 Death2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, p. e61828-Article in journal (Refereed)
    Abstract [en]

    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.

  • 26.
    Ngamjariyawat, Anongnad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Turpaev, Kyril
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Coculture of Insulin-Producing RIN5AH Cells With Neural Crest Stem Cells Protects Partially Against Cytokine-Induced Cell Death2012In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 41, no 3, p. 490-492Article in journal (Refereed)
  • 27.
    Olerud, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kanaykina, Nadegda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Vasilovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    King, Dale
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Neural crest stem cells increase beta cell proliferation and improve islet function in co-transplanted murine pancreatic islets2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 12, p. 2594-2601Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Long-term graft survival after islet transplantation to patientswith type 1 diabetes is insufficient, necessitating the development of newstrategies to enhance transplant viability. Here we investigated whetherco-transplantation of neural crest stem cells (NCSCs) with islets improves islet survival and function in normoglycaemic and diabetic mice. METHODS: Islets alone or together with NCSCs were transplanted under the kidney capsule tonormoglycaemic or alloxan-induced diabetic mice. Grafts were analysed for size,proliferation, apoptosis and insulin release. In diabetic recipients bloodglucose levels were examined before and after graft removal. RESULTS: In mixedtransplants NCSCs actively migrated and extensively associated withco-transplanted pancreatic islets. Proliferation of beta cells was markedlyincreased and transplants displayed improved insulin release in normoglycaemicmice compared with those receiving islet-alone transplants. Mixed grafts survivedsuccessfully and partially restored normoglycaemia in alloxan-induced diabeticmice. CONCLUSIONS/INTERPRETATION: Co-grafting of NCSCs with pancreatic isletsimproved insulin release in mixed transplants and enhanced beta cellproliferation, resulting in increased beta cell mass. This co-transplantationmodel offers an opportunity to restore neural-islet interactions and improveislet functions after transplantation.

  • 28.
    Tao, Ran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Glial cell responses, complement and apolipoprotein J expression following axon injury in the neonatal rat1999In: Journal of Neurocytology, ISSN 0300-4864, E-ISSN 1573-7381, Vol. 28, no 7, p. 559-570Article in journal (Refereed)
    Abstract [en]

    Immature motoneurons are highly susceptible to degeneration following axon injury. The response of perineuronal glia to axon injury may significantly influence neuronal survival and axon regeneration. We have examined the central reactions to neonatal facial nerve transection with emphasis on the expression of complement component C3 (C3) and the multifunctional apolipoprotein J (ApoJ). Axotomy was performed on one-day-old rats. Animals were perfused from eight hours to two weeks after the lesion. The astroglial marker, glial fibrillary acidic protein (GFAP) was increased from one day and the microglial marker OX-42 from two days after injury. ApoJ immunoreactivity was increased in axotomized neuronal perikarya and astroglial cells from one day postaxotomy, but no C3 immunoreactive profiles were found at any postoperative survival time. Cell proliferation as judged by bromodeoxyuridine labeling and immunoreactivity for the cyclin Ki-67 antigen (antibody MIB5) occurred only at two days after injury. Double immunostaining revealed that the vast majority of proliferating cells were microglia, although occasional cells double labeled astrocytes were found as well. Our results indicate that the non-neuronal response in neonatal animals differ from that of adult ones as follows: 1) microglia transform rapidly into phagocytes in parallel with the degeneration of axotomized neurons, 2) despite the presence of neuronal degeneration, no expression of C3 was found, and the upregulation of the expression of the complement C3 receptor (CR3) is delayed, 3) ApoJ is strongly upregulated in perineuronal astrocytes as well as in the axotomized motoneurons. The marked upregulation of ApoJ in both instances suggests a general role of this protein in the neuronal response to axotomy.

  • 29.
    Tao, Ran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Influence of FK506, cyclosporin A, testosterone and nimodipine on motoneuron survival following axotomy1998In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 12, no 4, p. 239-246Article in journal (Refereed)
    Abstract [en]

    Injury to immature motoneurons results in extensive nerve cell death. Avulsion injury in adult animals has a similar effect. Rescuing injured neurons from degeneration and death is a prerequisite for succesful functional recovery. Here, we have explored the possible survival promoting effect of the immunosuppressant agents FK506 and cyclosporin A, the calcium channel blocker nimodipine as well testosterone on axotomized neonatal facial motoneurons. In addition, we examined the effect of cyclosporin A and Nimodipine, a calcium channel blocker, on survival of adult motoneurons following hypoglossal nerve avulsion. FK506 and cyclosporin A were administered intraperitoneally, testosterone intramuscularly and Nimodipine via the food. After the appropriate postoperative survival periods, the number of surviving facial or hypoglossal motoneurons respectively was calculated. FK506 and Cyclosporin A were found to enhance facial motoneuron survival following neonatal axotomy. Cyclosporin A and Nimodipine were found to promote motoneuron survival in adult rats after hypoglossal nerve avulsion. Nimodipine possibly also reduced motoneuron death in neonatal rats twenty-one days after facial nerve transsection, but failed to rescue motoneurons in neonatal rats during the first seven days after nerve injury. Treatment with testosterone was ineffective in preventing neonatal facial motoneurons from axotomy-induced death at seven days postaxotomy. The restults indicate that motoneuron degeneration can be counteracted to a large extent by immunosuppressant agents as well as by calcium channel blockers. Taken together with findings form previous studies, we conclude that motoneuron survival following axotomy can be promoted by a variety of endogenous and exogenous molecules acting on different cellular mechanisms.

  • 30.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Adult motor neurons show increased susceptibility to axotomy-induced death in mice lacking clusterin2005In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 21, no 7, p. 2024-2028Article in journal (Refereed)
    Abstract [en]

    Clusterin is a highly conserved, amphiphatic glycoprotein present in most tissues. It has been shown to be involved in the regulation of lipid transportation, clearance of cellular debris from the extracellular space and intracellular signal transduction. Clusterin is markedly up-regulated after neural injury but the functional significance of this response is unclear. Here, we show that clusterin up-regulation is substantially greater in hypoglossal motor neurons after hypoglossal nerve avulsion compared with nerve transection. Quantitative analyses of motor neuron numbers after the same lesions in clusterin(-/-) and clusterin(+/+) mice showed significantly larger numbers of surviving motor neurons in clusterin(+/+) mice. These results suggest that clusterin has a neuroprotective role after axotomy.

  • 31.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Megalin deficiency induces critical changes in early glial development in mouse spinal cord2008In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 19, no 5, p. 559-563Article in journal (Refereed)
    Abstract [en]

    Low density lipoprotein receptor-related protein, megalin, is a multifunctional lipoproptein receptor expressed by absorptive epithelia for endocytosis of numerous ligands. Megalin is widely expressed during embryonic life and is essential for development of the nervous system as evidenced by severe forebrain abnormalities in megalin (-/-). Here, we investigated the influence of megalin deficiency on prenatal spinal cord development in mice. In contrast to wild-type mice, cells expressing Olig2 and NG2, that is, oligodendroglial precursor cells, are absent from embryonic stage E16 in megalin (-/-) mice. At the end of prenatal development, there is a failure in vertebral development, and the number of astrocytes are markedly reduced in megalin (-/-) mice. These findings indicate that megalin is essential in astro-oligodendroglial interactions during development of the spinal cord.

  • 32.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Fex-Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Valsecchi, Isabel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Charnay, Yves
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Extracellular clusterin promotes neuronal network complexity in vitro2008In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 19, no 15, p. 1487-1491Article in journal (Refereed)
    Abstract [en]

    Clusterin (apolipoprotein J), a highly conserved amphiphatic glycoprotein and chaperone, has been implicated in a wide range of physiological and pathological processes. As a secreted protein, clusterin has been shown to act extracellularly where it is involved in lipid transportation and clearance of cellular debris. Intracellularly, clusterin may regulate signal transduction and is upregulated after cell stress. After neural injury, clusterin may be involved in nerve cell survival and postinjury neuroplasticity. In this study, we investigated the role of extracelullar clusterin on neuronal network complexity in vitro. Quantitative analysis of clustrin-treated neuronal cultures showed significantly higher network complexity. These findings suggest that in addition to previously demonstrated neuroprotective roles, clusterin may also be involved in neuronal process formation, elongation, and plasticity.

  • 33.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fex Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Gyllencreutz, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Low density lipoprotein-related protein-2/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter2006In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 83, no 5, p. 864-873Article in journal (Refereed)
    Abstract [en]

    Lipoprotein receptor-related protein-2 (LRP2)/megalin is a member of the low density lipoprotein receptor (LDLR) family, and is essential in absorptive epithelia for endocytosis of lipoproteins, low molecular weight proteins, cholesterol and vitamins, as well as in cellular signaling. Previous studies have shown megalin expression in ependymal cells and choroid plexus. We have investigated megalin expression in the spinal cord of postnatal mice with immunohistochemistry and immunoblot. Antibodies recognizing either the cytoplasmic tail (MM6) or the extracellular domain (E11) of megalin labeled oligodendrocytes in the spinal cord white matter, in parallel with myelination. MM6 antibodies, predominantly labeled the nuclei, whereas E11 antibodies labeled the cytoplasm of these cells. MM6 antibodies labeled also nuclei of oligodendrocytes cultured from embryonic mouse spinal cord. Immunoblots of spinal cord showed intact megalin, as well as its carboxyterminal fragment, the part remaining after shedding of the extracellular domain of megalin. Megalin-immunoreactive oligodendrocytes also expressed presenilin 1, an enzyme responsible for gamma-secretase mediated endodomain cleavage. These findings show that spinal cord oligodendrocytes are phenotypically different from those in the brain, and indicate that megalin translocates signals from the cell membrane to the nucleus of oligodendrocytes during the formation and maintenance of myelin of long spinal cord pathways.

  • 34.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Aldskogius, Hakan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Low-density lipoprotein receptor-related protein (LRP)-2/megalin is transiently expressed in a subpopulation of neural progenitors in the embryonic mouse spinal cord2005In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 492, no 2, p. 123-131Article in journal (Refereed)
    Abstract [en]

    The lipoprotein receptor LRP2/megalin is expressed by absorptive epithelia and involved in receptor-mediated endocytosis of a wide range of ligands. Megalin is expressed in the neuroepithelium during central nervous system (CNS) development. Mice with homozygous deletions of the megalin gene show severe forebrain abnormalities. The possible role of megalin in the developing spinal cord, however, is unknown. Here we examined the spatial and temporal expression pattern of megalin in the embryonic mouse spinal cord using an antibody that specifically recognizes the cytoplasmic part of the megalin molecule. In line with published data, we show expression of megalin in ependymal cells of the central canal from embryonic day (E)11 until birth. In addition, from E11 until E15 a population of cells was found in the dorsal part of the developing spinal cord strongly immunoreactive against megalin. Double labeling showed that most of these cells express vimentin, a marker for immature astrocytes and radial glia, but not brain lipid binding protein (BLBP), a marker for radial glial cells, or glial fibrillary acidic protein (GFAP), a marker for mature astrocytes. These findings indicate that the majority of the megalin-positive cells are astroglial precursors. Megalin immunoreactivity was mainly localized in the nuclei of these cells, suggesting that the cytoplasmic part of the megalin molecule can be cleaved following ligand binding and translocated to the nucleus to act as a transcription factor or regulate other transcription factors. These findings suggest that megalin has a crucial role in the development of astrocytes of the spinal cord.

  • 35. Åkesson, Elisabet
    et al.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kanykina, Nadegda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Long-term survival, robust neuronal differentiation, and extensive migration of human forebrain stem/progenitor cells transplanted to the adult rat dorsal root ganglion cavity2008In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 17, no 10-11, p. 1115-1123Article in journal (Refereed)
    Abstract [en]

    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.

1 - 35 of 35
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