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  • 1.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Animal models of spinal cord repair2012Collection (editor) (Other academic)
  • 2.
    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.

  • 3.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Microglia in neuroregeneration2001In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 54, no 1, p. 40-46Article in journal (Refereed)
    Abstract [en]

    Microglia has the potential to produce and release a range of factors that directly and/or indirectly promote regeneration in the injured nervous system. The overwhelming evidence indicates, however, that this potential is generally not expressed in vivo. Activated microglia may enhance neuronal degeneration following axotomy, thereby counteracting functional recovery. Microglia does not seem to contribute significantly to axonal outgrowth after peripheral nerve injury, since this process proceeds uneventful even if perineuronal microglia is eliminated. The phagocytic phenotype of microglia is highly suppressed during Wallerian degeneration in the central nervous system. Therefore, microglia is incapable of rapid and efficient removal of myelin debris and its putative growth inhibitory components. In this way, microglia may contribute to regeneration failure in the central nervous system. Structural and temporal correlations are compatible with participation by perineuronal microglia in axotomy-induced shedding of presynaptic terminals, but direct evidence for such participation is lacking. Currently, the most promising case for a promoting effect on neural repair by activated microglia appears to be as a mediator of collateral sprouting, at least in certain brain areas. However, final proof for a critical role of microglia in these instances is still lacking. Results from in vitro studies demonstrate that microglia can develop a regeneration supportive phenotype. Altering the microglial involvement following neural injury from a typically passive or even counterproductive state and into a condition where these cells are actively supporting regeneration and plasticity is, therefore, an exciting challenge and probably a realistic goal.

  • 4.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Regulation of microglia: potential new drug targets in the CNS.2001In: Expert opinion on therapeutic targets, ISSN 1472-8222, E-ISSN 1744-7631, Vol. 5, no 6, p. 655-668Article in journal (Refereed)
    Abstract [en]

    Microglia respond to any disturbance in the CNS which poses a threat to physiological homeostasis. Although these responses are secondary, mainly to neuronal alterations, the way the microglial response evolves in many situations promotes further damage to the CNS. The list of clinical conditions in which this situation is a major problem is continuously growing and includes neurodegenerative diseases, stroke, trauma, demyelinating disorders and neuropathic pain. The significance of microglia for the pathogenesis of neurological and neuropsychiatric conditions has led to a rapidly expanding search for therapeutic possibilities to regulate microglial activity. As will be clear from this review, treatments which are currently available appear to offer some positive effects but are still far from satisfactory. A major challenge is to understand the mechanisms that determine whether activated microglia will develop into a cytotoxic or a cytoprotective component.

  • 5.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. neuroanatomi.
    Repairing CNS myelin: astrocytes have to do their jobs2005In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 192, no 1, p. 7-10Article in journal (Refereed)
  • 6.
    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.

  • 7.
    Aldskogius, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Central neuron-glial and glial-glial interactions following axon injury1998In: Progress in Neurobiology, ISSN 0301-0082, E-ISSN 1873-5118, Vol. 55, no 1, p. 1-26Article in journal (Refereed)
    Abstract [en]

    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.

  • 8.
    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.

  • 9.
    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.

  • 10.
    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.

  • 11.
    Brännvall, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wallenquist, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg-Nilsson, Karin
    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. Neuroanatomi.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Central nervous system stem/progenitor cells form neurons and peripheral glia after transplantation to the dorsal root ganglion.2006In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 17, no 6, p. 623-628Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Fundin, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Silos-Santiago, I
    Ernfors, Patrik
    Fagan, A.M.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    DeChiara, T.M.
    Phillips, H
    Barbacid, M
    Yancopoulos, G.D.
    Rice, Frank L.
    Differential dependency of developing mechanoreceptors on neurotrophins, trk receptors, and p75LNGFR1997In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 190, no 1, p. 94-116Article in journal (Refereed)
    Abstract [en]

    The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75. Specimens were sacrificed at birth and at 1, 2, and 4 weeks for each type of mutation as well as at 11 weeks and 1 year for p75 and trkC mutations, respectively. Our results demonstrate several major concepts about the role of neurotrophins in the development of cutaneous mechanoreceptors that are supplied by medium to large caliber myelinated afferents. First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor. Second, consistent with the various affinities for particular trk receptors, the elimination of NGF, BDNF, and NT-3 has an impact comparable to or more complex than the absence of their most specific high-affinity receptors: trkA, trkB, and trkC, respectively. These complexities include potential NT-3 signaling through trkA and trkB to support some neuronal survival. Third, most types of afferents are dependent on a different combination of neurotrophins and receptors for their survival: reticular and transverse lanceolate afferents are dependent upon NT-3, NGF, and trkA; Ruffini afferents upon BDNF and trkB; longitudinal lanceolate afferents upon NGF, trkA, BDNF, and trkB; and Merkel afferents on NGF, trkA, NT-3, trkC, and p75. NT-4 has no obvious detrimental impact on the mechanoreceptor development in the presence of BDNF. Fourth, NT-4 and BDNF signaling through trkB may suppress Merkel innervation and NT-3 signaling through trkC may suppress Ruffini innervation. Finally, regardless of the neurotrophin/receptor dependency for afferent survival and neurite outgrowth, NT-3 has an impact on the formation of all the sensory endings. In the context of these findings, indications of competitive and suppressive interactions that appear to regulate the balance of innervation density among the various sets of innervation were evident.

  • 13. Fundin, Bengt T.
    et al.
    Arvidsson, Jan
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Johansson, Olle
    Rice, Susan
    Rice, Frank L
    A comprehensive immunofluorescence and lectin binding analysis of intervibrissal fur innervation in the mystacial pad of the rat1997In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 385, no 2, p. 185-206Article in journal (Refereed)
    Abstract [en]

    The innervation of the intervibrissal fur in the mystacial pad of the rat and mouse wasexamined by immunofluorescence with a wide variety of antibodies for neuronal relatedstructural proteins, enzymes, and peptides as well as for lectin binding histofluorescence with Griffonia simplicifolia (GSA). Anti-protein gene product 9.5 (PGP) immunofluorescencelabeled all sets of axons and endings. The innervation in the upper dermis and epidermis wasdistributed through a four tiered dermal plexus. From deep to superficial, the second tier wasthe source of all apparent myelinated mechanorceptors, the third tier of nearly all thepeptidergic and GSA binding innervation, and the fourth tier of nonpeptidergic GSA negativeinnervation (peptide-/GSA-). Three types of mechanoreceptors—Merkel, transverse lanceolate,and longitudinal lanceolate endings—innervated guard hair follicles. All had similarlabeling characteristics for 160 kDa and 200 kDa neurofilament subunits, peripherin,carbonic anhydrase, synaptophysin, and S100. Palisades of longitudinal lanceolate endingswere part of piloneural complexes along circumferentially oriented sets of transverselanceolate endings, peptidergic free nerve endings (FNEs), and peptide-/GSA- FNEs. Thelongitudinal lanceolate endings were the only mechanoreceptors in the mystacial pad that haddetectable calcitonin gene-related peptide. The epidermis contained four types of unmyelinatedendings: simple free nerve endings (FNEs), penicillate endings, cluster endings and bushendings. Only the simple FNEs were clearly peptidergic. Virtually all others were peptide-/GSA-. Each bush ending was actually an intermingled cluster of endings formed by severalunmyelinated axons and occasionally anAd axon. In contrast to the other unmyelinated innervationto the epidermis, bush endings labeled with an antibody against the Schwann cell protein S100. Thenecks and mouths of follicles, as well as superficial vasculature, were innervated by a mixture of unmyelinated peptidergic and/or GSA labeled sensory and sympathetic axons. Small presumptivesweat glands were innervated by three sets of peptidergic axons of which one was immunoreactivefor somatostatin. Potential functions of the various sets of innervation are discussed.

  • 14.
    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.

  • 15. Grant, Gunnar
    et al.
    Hollander, Horstmar
    Aldskogius, Håkan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Neuroanatomi.
    Suppressive silver methods - a tool for identifying axotomy-induced neuron degeneration2004In: Brain Res Bull, Vol. 4, no 62, p. 261-269Article in journal (Refereed)
  • 16.
    Hoeber, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    König, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhou, Chunfang
    Nanologica AB , Södertälje, Sweden.
    Pankratova, Stanislava
    Univ Copenhagen, Inst Neurosci & Pharmacol, Copenhagen, Denmark.
    Åkesson, Elisabet
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord2017In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 14, p. 1065-1077Article in journal (Refereed)
    Abstract [en]

    Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.

  • 17.
    Hoeber, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    König, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Du, Zhongwei
    Gallo, Alessandro
    Hermans, Emmanuel
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Shortland, Peter
    Zhang, Su-Chun
    Deumens, Ronald
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10666Article in journal (Refereed)
    Abstract [en]

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

  • 18.
    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.

  • 19. 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.

  • 20.
    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.

  • 21.
    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.

  • 22.
    Latini, Francesco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hjortberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Ryttlefors, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    The Classical Pathways of Occipital Lobe Epileptic Propagation Revised in the Light of White Matter Dissection2015In: Behavioural Neurology, ISSN 0953-4180, E-ISSN 1875-8584, article id 872645Article in journal (Refereed)
    Abstract [en]

    The clinical evidences of variable epileptic propagation in occipital lobe epilepsy (OLE) have been demonstrated by several studies. However the exact localization of the epileptic focus sometimes represents a problem because of the rapid propagation to frontal, parietal, or temporal regions. Each white matter pathway close to the supposed initial focus can lead the propagation towards a specific direction, explaining the variable semiology of these rare epilepsy syndromes. Some new insights in occipital white matter anatomy are herein described by means of white matter dissection and compared to the classical epileptic patterns, mostly based on the central position of the primary visual cortex. The dissections showed a complex white matter architecture composed by vertical and longitudinal bundles, which are closely interconnected and segregated and are able to support specific high order functions with parallel bidirectional propagation of the electric signal. The same sublobar lesions may hyperactivate different white matter bundles reemphasizing the importance of the ictal semiology as a specific clinical demonstration of the subcortical networks recruited. Merging semiology, white matter anatomy, and electrophysiology may lead us to a better understanding of these complex syndromes and tailored therapeutic options based on individual white matter connectivity.

  • 23.
    Latini, Francesco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hjortberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Ryttlefors, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    The use of a cerebral perfusion and immersion-fixation process for subsequent white matter dissection2015In: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 253, p. 161-169Article in journal (Refereed)
    Abstract [en]

    Background: The Klingler's method for white matter dissection revolutionized the study of deep cerebral anatomy. Although this technique made white matter dissection more feasible and widely used, it still presents some intrinsic limitations. New method: We evaluated the quality of different methods for specimen preparation based on an intra-carotidal formalin perfusion fixation process. Ten post-mortem human hemispheres were prepared with this method and dissected in a stepwise manner. Results: The homogeneous and rapid fixation of the brain allowed documentation of several fine additional anatomical details. Intra-cortical white matter terminations were described during the first stage of dissection on each specimen. No limitations were encountered during dissection of the major associative bundles. On the contrary, the quality of the fixation of the specimens made it possible to isolate them en bloc. One of the most complex and deep bundles (accumbo-frontal fasciculus) was dissected without technical limitations. Deep vascular structures were very well preserved and dissected within the white matter until their sub-millimetric terminations. Comparison with existing method: Short time for preparation, a more homogeneous fixation, no technical limitation for a detailed description of superficial and deep white matter anatomy, the possibility to dissect with a single technique the fibre organization and the white matter vascular architecture are the advantages reported with the perfusion fixation. Conclusion: These results provide encouraging data about the possibility to use a perfusion fixation process, which may help in improving the quality of white matter dissection for research, didactic purposes and surgical training.

  • 24.
    Latini, Francesco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Mårtensson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Hjortberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Ryttlefors, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study.2017In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, no 1675, p. 102-115, article id S0006-8993(17)30386-4Article in journal (Refereed)
    Abstract [en]

    The inferior longitudinal fascicle (ILF) is one of the major occipital-temporal association pathways. Several studies have mapped its hierarchical segmentation to specific functions. There is, however, no consensus regarding a detailed description of ILF fibre organisation. The aim of this study was to establish whether the ILF has a constant number of subcomponents. A secondary aim was to determine the quantitative diffusion proprieties of each subcomponent and assess their anatomical trajectories and connectivity patterns. A white matter dissection of 14 post-mortem normal human hemispheres was conducted to define the course of the ILF and its subcomponents. These anatomical results were then investigated in 24 right-handed, healthy volunteers using in vivo diffusion tensor imaging (DTI) and streamline tractography. Fractional anisotropy (FA), volume, fibre length and the symmetry coefficient of each fibre group were analysed. In order to show the connectivity pattern of the ILF, we also conducted an analysis of the cortical terminations of each segment. We confirmed that the main structure of the ILF is composed of three constant components reflecting the occipital terminations: the fusiform, the lingual and the dorsolateral-occipital. ILF volume was significantly lateralised to the right. The examined indices of ILF subcomponents did not show any significant difference in lateralisation. The connectivity pattern and the quantitative distribution of ILF subcomponents suggest a pivotal role for this bundle in integrating information from highly specialised modular visual areas with activity in anterior temporal territory, which has been previously shown to be important for memory and emotions.

  • 25. 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.

  • 26.
    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.

  • 27.
    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.

  • 28.
    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.

  • 29.
    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.

  • 30. 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.

  • 31. 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.

  • 32. 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.

  • 33. Rice, Frank
    et al.
    Albers, K
    Davis, Brian
    Silos-Santiago, I
    Wilkinson, GA
    LeMaster, GA
    Ernfors, Patrik
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Human Anatomy.
    Phillips, HS
    Barbacid, M
    DeChiara, TM
    Yancopoulos, GD
    Dunne, CE
    Fundin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Differential dependency of unmyelinated and A delta epidermal and upper dermal innervation on neurotrophins, trk receptors, and p75LNGFR1998In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 198, no 1, p. 57-81Article in journal (Refereed)
    Abstract [en]

    The impact of the nerve growth factor (NGF) family of neurotrophins and their receptors was examined on the cutaneous innervation in the mystacial pads of mice. Ten sets of unmyelinated and thinly myelinated sensory and autonomic innervation were evaluated that terminated in the epidermis, upper dermis, and upper part of the intervibrissal hair follicles. Mystacial pads were analyzed from newborn to 4-week-old mice that had homozygous functional deletions of the genes for NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), tyrosine kinase (trk) A, trkB, trkC, or p75. Mystacial pads were also analyzed in adult transgenic mice that had overproduction of NGF, BDNF, or NT-3 driven by a keratin promoter gene. The innervation was revealed by using immunofluorescence and immunocytochemistry with antibodies for protein gene product (PGP) 9.5, calcitonin gene-related product (CGRP), substance P (SP), galanin (GAL), neuropeptide Y (NPY), tyrosine hydroxylase (TH), and a neurofilament protein. The cumulative results indicated that NGF/trkA signaling plays a major role in the outgrowth and proliferation of sensory axons, whereas NT-3/ trkA signaling plays a major role in the formation of sensory endings. TrkC is also essential for the development of three sets of trkA-dependent sensory innervation that coexpress CGRP, SP, and GAL. Another set of sensory innervation that only coexpressed CGRP and SP was solely dependent upon NGF and trkA. Surprisingly, most sets of trkA-dependent sensory innervation are suppressed by trkB perhaps interacting with p75. BDNF and NT-4 appear to mediate this suppressing effect in the upper dermis and NT-4 in the epidermis. In contrast to sensory innervation, sympathetic innervation to the necks of intervibrissal hair follicles depends upon NGF/trkA signaling interacting with p75 for both the axon outgrowth and ending formation. Although NT-3/trkA signaling is essential for the full complement of sympathetic neurons, NT-3 is detrimental to the formation of sympathetic terminations to the necks of hair follicles. TrkB signaling mediated by BDNF but not NT-4 also suppresses these sympathetic terminations. One sparse set of innervation, perhaps parasympathetic, terminating at the necks of hair follicles is dependent solely upon NT-3 and trkC. Taken together, our results indicate that the innervation of the epidermis, upper dermis, and the upper portion of hair follicles is regulated by a competitive balance between promoting and suppressing effects of the various neurotrophins.

  • 34.
    Rice, Frank L
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fundin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Arvidsson, Jan
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Johansson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    A comprehensive immunofluorescence and lectin binding analysis of vibrissal follicle sinus complex innervation in the mystacial pad of the rat1997In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 385, no 2, p. 149-184Article in journal (Refereed)
    Abstract [en]

    The innervation of the vibrissal follicle sinus complexes (FSCs) in the mystacial pad of the rat was examined by lectin binding histofluorescence with the B subunit of Griffonia simplicifolia (GSA) and by immunofluorescence with a wide variety of antibodies for neuronal related structural proteins, enzymes, and peptides. Only anti-protein gene product 9.5 labeled all sets of innervation. Several types of mechanoreceptors were distributed to specific different targets by medium to large caliber myelinated axons. All were positive for 200 kDa neurofilament subunit, peripherin, and carbonic anhydrase. Their endings expressed synaptophysin. Labeling for the 160 kDa neurofilament subunit, calbindin, and parvalbumin varied. Anti-Schwann cell protein S100 was completely co-extensive with the axons, terminal arbors, and endings of the mechanoreceptor afferents including Merkel innervation. At least 15 different sets of unmyelinated innervation were evident based upon distribution and labeling characteristics. They consisted of four basic types: 1) peptidergic; 2) GSA binding; 3) peptidergic and GSA binding; and 4) nonpeptidergic and GSA negative (peptide-/GSA-). Previous studies had not revealed that several major sets of unmyelinated innervation were peptide-/GSA-. The unmyelinated innervation had detectable peripherin but not 160 kDa or 200 kDa neurofilament subunits. GSA-positive axons uniquely lacked anti-S100 immunoreactivity. The dense circumferentially oriented unmyelinated innervation of the inner conical body contained major sets of peptide-/GSA- and GSA innervation as well as a smaller peptidergic GSA component. A small contingent of sympathetic and possibly parasympathetic innervation was affiliated with microvasculature in the FSCs. This study confirms and refutes some previous hypotheses about biochemical and morphological relationships between peripheral innervation and sensory ganglion cells.

  • 35.
    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.

  • 36.
    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.

  • 37.
    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.

  • 38.
    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.

  • 39.
    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.

  • 40.
    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.

  • 41. 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.

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