Mikael Wiberg

Umeå University, Umeå, Västerbotten, Sweden

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Publications (128)290.73 Total impact

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    ABSTRACT: Botulinum toxin A (BoNT-A) injections for treatment of spasticity in patients with cerebral palsy (CP) have been used for about two decades. The treatment is considered safe but a low frequency of adverse events (AE) has been reported. A good method to report AEs is necessary to verify the safety of the treatment. We decided to use an active surveillance of treatment-induced harm using a questionnaire we created. We studied the incidence of reported AEs and side effects in patients with CP treated with BoNT-A. We investigated the relationship between the incidence of AEs or side effects and gender, age, weight, total dose, dose per body weight, Gross Motor Function Classification System (GMFCS) and number of treated body parts. Seventy-four patients with CP participated in our study. In 54 (51%) of 105 BoNT-A treatments performed in 45 (61%) patients, there were 95 AEs and side effects reported, out of which 50 were generalized and/or focal distant. Severe AEs occurred in three patients (4%), and their BoNT-A treatment was discontinued. Consecutive collection of the AE and side-effect incidence using our questionnaire can increase the safety of BoNT-A treatment in patients with CP.
    Toxins 11/2015; 7(11):4645-4654. DOI:10.3390/toxins7114645 · 2.94 Impact Factor
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    ABSTRACT: Traumatic injury to the central nervous system (CNS) is further complicated by an increase in secondary neuronal damage imposed by activated microglia/macrophages. MicroRNA-124 (miR-124) is responsible for mouse monocyte quiescence and reduction of their inflammatory cytokine production. We describe the formulation and ex vivo transfection of chitosan/miR-124 polyplex particles into rat microglia and the resulting reduction of reactive oxygen species (ROS) and TNF-α and lower expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia cells. Alternatively particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury 72h post injection. Microinjections of chitosan/miR-124 particles significantly reduced the number of ED-1 positive macrophages in the injured spinal cord. Taken together, these data present a potential treatment technique to reduce inflammation for a multitude of CNS neurodegenerative conditions.
    Nanomedicine: nanotechnology, biology, and medicine 11/2015; DOI:10.1016/j.nano.2015.10.011 · 6.16 Impact Factor
  • Paul J Kingham · Adam J Reid · Mikael Wiberg ·
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    ABSTRACT: Peripheral nerve injury is a relatively commonly occurring trauma which seriously compromises the quality of life for many individuals. There is a major need to devise new treatment strategies, and one possible approach is to develop cellular therapies to bioengineer new nerve tissue and/or modulate the endogenous regenerative mechanisms within the peripheral nervous system. In this short review we describe how stem cells isolated from adipose tissue could be a suitable element of this approach. We describe the possible mechanisms through which the stem cells might exert a positive influence on peripheral nerve regeneration. These include their ability to differentiate into cells resembling Schwann cells and their secretion of a plethora of neurotrophic growth factors. We also review the literature describing the effects of these cells when tested using in vivo peripheral nerve injury models. © 2015 S. Karger AG, Basel.
    Cells Tissues Organs 03/2015; 200(1). DOI:10.1159/000369336 · 2.14 Impact Factor
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    ABSTRACT: Object: The dyskinetic subtype of cerebral palsy is difficult to manage, and there is no established gold standard for treatment. External rotation of the shoulder(s) is often managed nonsurgically using injections of botulinum toxin A into the external rotator muscles. This article reports a new surgical technique for managing external rotation when botulinum toxin A treatment is not sufficient or possible. Methods: Six patients with dyskinetic cerebral palsy underwent denervation of the infraspinatus muscle and release of the posterior part of the deltoid muscle. Postoperative questionnaires were given to the patients/caregivers, and video recordings were made both pre- and postoperatively. Preoperative and postoperative Assisting Hand Assessment was possible in only 1 case. Results: Five patients were very satisfied with their outcome. Four patients' video recordings showed improvement in their condition. One patient developed postoperative complications. Conclusions: The results indicate that denervation of the infraspinatus muscle and posterior deltoid release can be an option for patients with dyskinetic cerebral palsy to manage external rotation of the shoulder when other treatment alternatives are insufficient.
    Journal of Neurosurgery Pediatrics 01/2015; 15(4):1-7. DOI:10.3171/2014.9.PEDS14223 · 1.48 Impact Factor
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    ABSTRACT: Peripheral nerve injuries are often associated with loss of nerve tissue and require a graft to bridge the gap. Autologous nerve grafts are still the 'gold standard' in reconstructive surgery but have several disadvantages, such as sacrifice of a functional nerve, neuroma formation and loss of sensation at the donor site. Bioengineered grafts represent a promising approach to address this problem. In this study, poly-3-hydroxybutyrate (PHB) strips were used to bridge a 10 mm rat sciatic nerve gap and their effects on long-term (12 weeks) nerve regeneration were compared. PHB strips were seeded with different cell types, either primary Schwann cells (SCs) or SC-like differentiated adipose-derived stem cells (dASCs) suspended in a fibrin glue matrix. The control group was PHB and fibrin matrix without cells. Functional and morphological properties of the regenerated nerve were assessed using walking track analysis, EMGs, muscle weight ratios and muscle and nerve histology. The animals treated with PHB strips seeded with SCs or dASCs showed significantly better functional ability than the control group. This correlated with less muscle atrophy and greater axon myelination in the cell groups. These findings suggest that the PHB strip seeded with cells provides a beneficial environment for nerve regeneration. Furthermore, dASCs, which are abundant and easily accessible, constitute an attractive cell source for future applications of cell therapy for the clinical repair of traumatic nerve injuries. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 12/2014; DOI:10.1002/term.1980 · 5.20 Impact Factor
  • Kai-Hei Tse · Lev N Novikov · Mikael Wiberg · Paul J Kingham ·
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    ABSTRACT: Adipose derived stem cells (ADSC) can be differentiated into Schwann cell-like cells which enhance nerve function and regeneration. However, the signalling mechanisms underlying the neurotrophic potential of ADSC remain largely unknown. In this study, we hypothesised that ADSC, upon stimulation with a combination of growth factors, could rapidly produce brain derived neurotrophic factor (BDNF) with a similar molecular mechanism to that functioning in the nervous system. Within 48 hours of stimulation, ADSC demonstrated potent neurotrophic effects on dorsal root ganglion neurons, at a magnitude equivalent to that of the longer term differentiated Schwann cell-like cells. Stimulated ADSC showed rapid up-regulation of the neuronal activity dependent promoter BDNF exon IV along with an augmented expression of full length protein encoding BDNF exon IX. BDNF protein was secreted at a concentration similar to that produced by differentiated Schwann cell-like cells. Stimulation also activated the BDNF expression gating transcription factor, cAMP responsive element binding (CREB) protein. However, blocking phosphorylation of CREB with the protein kinase A small molecule inhibitor H89 did not suppress secretion of BDNF protein. These results suggest rapid BDNF production in ADSC is mediated through multiple compensatory pathways independent of, or in addition to, the CREB neuronal activation cascade.
    Experimental Cell Research 09/2014; 331(1). DOI:10.1016/j.yexcr.2014.08.034 · 3.25 Impact Factor
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    ABSTRACT: INTRODUCTION: Peripheral nerve injuries affect 3% of trauma patients1 . In cases of gap injuries, an autologous nerve graft is the gold standard technique used to repair the defect. Artificial nerve conduits constructed from either natural or synthetic materials have been developed but their ability to promote regeneration is inferior to nerve grafts 2 . Advanced fabrication techniques might enable the production of more precisely designed conduits with suitable chemical properties to better support axon growth and Schwann cell biocompatibility. In this study we have compared a new 3D-structured polycaprolactone (PCL) conduit with simple tubular constructs made from fibrin glue. METHODS: Caprolactone pre-polymer was microwave synthesised, methcrylate functionalised and then UV cured into 3D structures via stereolithography (PCL conduit)3 . Tubular fibrin conduits were moulded from two-compound fibrin glue (TisseelTM Duo Quick; Baxter)4 . The constructs were used to repair a 10mm rat sciatic nerve gap. Regeneration was compared with autologous reverse nerve grafts at 3 weeks. RESULTS: In vitro testing demonstrated cellular adhesions and neurite outgrowth on the caprolactone material. In vivo, the 3D structured PCL conduits supported a 6-fold higher level of axon regeneration into the distal stump, compared with the fibrin conduit. Numerous regenerating axons were adherent to the wall of the PCL conduit, often in close association to the infiltrating Schwann cells (Figure 1). The Schwann cell ingrowth was more extensive in the PCL conduit compared with the fibrin conduit. Both conduits supported early vascularisation and RECA-1 positive endothelial cells also attached to the walls of the PCL conduit. DISCUSSION & CONCLUSIONS: In summary, the 3D micro-printed PCL conduit demonstrated the usefulness of photocurable, degradable polymers as a tool to manufacture a new generation of conduits in peripheral nerve repair. REFERENCES: 1. Pfister BJ et al. (2011) Critical reviews in biomedical engineering. 39:81-124. 2. Bell JHA, Haycock JW (2012). Tissue engineering. 18(2): 116-128. 3. Koroleva A et al. (2012) Biofabrication. 23; 4(2):025005. 4. Kingham PJ et al. (2014) Stem cells and Development. 1;23(7):741-54 ACKNOWLEDGMENTS: This study was supported by the Swedish Research Council, European Union, Umeå University, the County of Vasterbotten, the NIHR i4i and the EPSRC, UK
    Tissue and Cell Engineering Society, Newcastle; 07/2014
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    ABSTRACT: Spinal cord injury triggers a cascade of degenerative changes leading to cell death and cavitation. Severed axons fail to regenerate across the scar tissue and are only capable of limited sprouting. In this study we investigated the effects of adult human adipose derived stem cells (ASC) on axonal regeneration following transplantation into the injured rat cervical spinal cord. ASC did not induce activation of astrocytes in culture and supported neurite outgrowth from adult rat sensory DRG neurons. After transplantation into the lateral funiculus 1mm rostral and caudal to the cervical C3-C4 hemisection, ASC continued to express BDNF, VEGF and FGF-2 for 3 weeks but only in animals treated with cyclosporine A. Transplanted ASC stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone with some terminal arborisations reaching the caudal spinal cord. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure of the lesion scar with numerous astrocytic processes extended into the middle of the trauma zone in a chain-like pattern and in close association with regenerating axons. The density of the astrocytic network was also significantly decreased. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the activity of OX42-positive microglial cells was markedly reduced. However, ASC did not support recovery of forelimb function. The results suggest that transplanted ASC can modify the structure of the glial scar and stimulate axonal sprouting.
    Stem cells and development 05/2014; 23(14). DOI:10.1089/scd.2013.0416 · 3.73 Impact Factor
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    ABSTRACT: Traumatic spinal cord injury induces a long-standing inflammatory response in the spinal cord tissue, leading to a progressive apoptotic death of spinal cord neurons and glial cells. We have recently demonstrated that immediate treatment with the antioxidants N-acetyl-cysteine (NAC) and acetyl-L-carnitine (ALC) attenuates neuroinflammation, induces axonal sprouting, and reduces the death of motoneurons in the vicinity of the trauma zone 4 weeks after initial trauma. The objective of the current study was to investigate the effects of long-term antioxidant treatment on the survival of descending rubrospinal neurons after spinal cord injury in rats. It also examines the short- and long-term effects of treatment on apoptosis, inflammation, and regeneration in the spinal cord trauma zone. Spinal cord hemisection performed at the level C3 induced a significant loss of rubrospinal neurons 8 weeks after injury. At 2 weeks, an increase in the expression of the apoptosis associated markers BAX and caspase 3, as well as the microglial cell markers OX42 and ED1, was seen in the trauma zone. After 8 weeks, an increase in immunostaining for OX42 and the serotonin marker 5HT was detected in the same area. Antioxidant therapy reduced the loss of rubrospinal neurons by approximately 50%. Treatment also decreased the expression of BAX, caspase 3, OX42 and ED1 after 2 weeks. After 8 weeks, treatment decreased immunoreactivity for OX42, whereas it was increased for 5HT. In conclusion, this study provides further insight in the effects of treatment with NAC and ALC on descending pathways, as well as short- and long term effects on the spinal cord trauma zone.
    Neuroscience 03/2014; 269. DOI:10.1016/j.neuroscience.2014.03.042 · 3.36 Impact Factor
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    ABSTRACT: Adipose derived stem cells (ASC) might in future be used to treat neurological disorders. In this study, the neurotrophic and angiogenic properties of human ASC were evaluated and their effects in a peripheral nerve injury model determined. Growth factor stimulation of the cells in vitro resulted in increased secretion of BDNF, GDNF, VEGF-A and angiopoietin-1 proteins. Conditioned medium from stimulated cells increased neurite outgrowth of dorsal root ganglia (DRG) neurons. Similarly, stimulated cells showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. ASC were seeded into a fibrin conduit which was used to bridge a 10mm rat nerve gap. After 2 weeks, the animals treated with control or stimulated ASC showed an enhanced axon regeneration distance. Stimulated cells evoked more total axon growth. Analysis of regeneration and apoptosis related gene expressions showed that both ASC and stimulated ASC enhanced GAP-43 and ATF-3 expression in the spinal cord and reduced c-jun expression in the DRG. Caspase-3 expression in the DRG was reduced by stimulated ASC. Both ASC and stimulated ASC also increased the vascularity of the fibrin nerve conduits. Thus, ASC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for nerve regeneration.
    Stem cells and development 10/2013; 23(7). DOI:10.1089/scd.2013.0396 · 3.73 Impact Factor
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    ABSTRACT: Extensive death of sensory neurons after nerve trauma depletes numbers of regenerating neurons, contributing to inadequate cutaneous innervation density and poor sensory recovery. Experimentally proven neuroprotective neo-adjuvant drugs require non-invasive in-vivo measures of neuron death to permit clinical trials. In animal models of nerve transection, MRI proved a valid tool for quantifying sensory neuron loss within dorsal root ganglia (DRG) by measuring consequent proportional shrinkage of respective ganglia. This system is investigated for clinical application after upper limb nerve injury and microsurgical nerve repair METHODS:: A 3.0 Tesla clinical Magnet was used to image and measure volume (Cavalieri principle) of C7-T1 DRG in un-injured volunteers (controls, n=14), hand amputees (unrepaired nerve injury, n=5), and early nerve repair patients (median and ulnar nerves transected, microsurgical nerve repair within 24 hours, n=4). MRI was well tolerated. Volumetric analysis was feasible in 74% of patients. Mean 14% volume reduction was found in amputees' C7 and C8 DRG (p<0.001 vs. controls). Volume loss was lower in median & ulnar nerve repair patients (mean 3% volume loss, p<0.01 vs. amputees), and varied between patients. T1 DRG volume remained unaffected. MRI provides non-invasive in-vivo assessment of DRG volume as a proxy clinical measure of sensory neuron death. The significant decrease found after unrepaired nerve injury provides indirect clinical evidence of axotomy-induced neuronal death. This loss was less after nerve repair, indicating neuroprotective benefit from early repair. Volumetric MRI has potential diagnostic applications, and is a quantitative tool for clinical trials of neuroprotective therapies.
    Neurosurgery 07/2013; 73(4). DOI:10.1227/NEU.0000000000000066 · 3.62 Impact Factor
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    ABSTRACT: Introduction: Functional muscle recovery after peripheral nerve injury is far from optimal, partly due to atrophy of the muscle arising from prolonged denervation. We hypothesized that injecting regenerative cells into denervated muscle would reduce this atrophy. Methods: A rat sciatic nerve lesion was performed, and Schwann cells or adipose-derived stem cells, untreated or induced to a "Schwann-cell-like" phenotype (dASC), were injected into the gastrocnemius muscle. Nerves were either repaired immediately or capped to prevent muscle reinnervation. One month later, functionality was measured using a walking track test, and muscle atrophy was assessed by examining muscle weight and histology. Results: Schwann cells and dASC groups showed significantly better scores on functional tests when compared with injections of growth medium alone. Muscle weight and histology were also significantly improved in these groups. Conclusion: Cell injections may reduce muscle atrophy and could benefit nerve injury patients.
    Muscle & Nerve 05/2013; 47(5). DOI:10.1002/mus.23662 · 2.28 Impact Factor
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    ABSTRACT: Despite advances in surgical techniques for peripheral nerve repair, functional restitution remains incomplete. The timing of surgery is one factor influencing the extent of recovery but it is not yet clearly defined how long a delay may be tolerated before repair becomes futile. In this study, rats underwent sciatic nerve transection before immediate (0) or 1, 3, or 6 months delayed repair with a nerve graft. Regeneration of spinal motoneurons, 13 weeks after nerve repair, was assessed using retrograde labeling. Nerve tissue was also collected from the proximal and distal stumps and from the nerve graft, together with the medial gastrocnemius (MG) muscles. A dramatic decline in the number of regenerating motoneurons and myelinated axons in the distal nerve stump was observed in the 3- and 6-months delayed groups. After 3 months delay, the axonal number in the proximal stump increased 2-3 folds, accompanied by a smaller axonal area. RT-PCR of distal nerve segments revealed a decline in Schwann cells (SC) markers, most notably in the 3 and 6 month delayed repair samples. There was also a progressive increase in fibrosis and proteoglycan scar markers in the distal nerve with increased delayed repair time. The yield of SC isolated from the distal nerve segments progressively fell with increased delay in repair time but cultured SC from all groups proliferated at similar rates. MG muscle at 3- and 6-months delay repair showed a significant decline in weight (61% and 27% compared with contra-lateral side). Muscle fiber atrophy and changes to neuromuscular junctions were observed with increased delayed repair time suggestive of progressively impaired reinnervation. This study demonstrates that one of the main limiting factors for nerve regeneration after delayed repair is the distal stump. The critical time point after which the outcome of regeneration becomes too poor appears to be 3-months.
    PLoS ONE 02/2013; 8(2):e56484. DOI:10.1371/journal.pone.0056484 · 3.23 Impact Factor
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    ABSTRACT: Clinical efficacy of stem cells for nerve repair is likely to be influenced by issues including donor age and in vitro expansion time. We isolated human mesenchymal stem cells (MSC) from bone marrow of young (16-18 years) and old (67-75 years) donors and analyzed their capacity to differentiate and promote neurite outgrowth from dorsal root ganglia (DRG) neurons. Treatment of MSC with growth factors (forskolin, basic fibroblast growth factor, platelet derived growth factor-AA and glial growth factor-2) induced protein expression of the glial cell marker S100 in cultures from young but not old donors. MSC expressed various neurotrophic factor mRNA transcripts. Growth factor treatment enhanced the levels of BDNF and VEGF transcripts with corresponding increases in protein release in both donor cell groups. MSC in co-culture with DRG neurons significantly enhanced total neurite length which, in the case of young but not old donors, was further potentiated by treatment of the MSC with the growth factors. Stem cells from young donors maintained their proliferation rate over a time course of 9 weeks whereas those from the old donors showed increased population doubling times. MSC from young donors, differentiated with growth factors after long-term culture, maintained their ability to enhance neurite outgrowth of DRG. Therefore, MSC isolated from young donors are likely to be a favourable cell source for nerve repair.
    PLoS ONE 09/2012; 7(9):e45052. DOI:10.1371/journal.pone.0045052 · 3.23 Impact Factor
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    ABSTRACT: Peripheral nerve injuries (PNI) are continuing to be an ever-growing socio-economic burden affecting mainly the young working population and the current clinical treatments to PNI provide a poor clinical outcome involving significant loss of sensation. Thus, our understanding of the underlying factors responsible for the extensive loss of the sensory cutaneous subpopulation in the dorsal root ganglia (DRG) that occurs following injury needs to be improved. The current investigations focus in identifying visual cues of mitochondria-related apoptotic events in the various subpopulations of sensory cutaneous neurons. Sensory neuronal subpopulations were identified using FastBlue retrograde labelling following axotomy. Specialised fluorogenic probes, MitoTracker Red and MitoTracker Orange, were employed to visualise the dynamic changes of the mitochondrial population of neurons. The results reveal a fragmented mitochondrial network in sural neurons following apoptosis, whereas a fused elongated mitochondrial population is present in sensory proprioceptive muscle neurons following tibial axotomy. We also demonstrate the neuroprotective properties of NAC and ALCAR therapy in vitro. The dynamic mitochondrial network breaks down following oxidative exposure to hydrogen peroxide (H(2)O(2)), but reinitiates fusion after NAC and ALCAR therapy. In conclusion, this study provides both qualitative and quantitative evidence of the susceptibility of sensory cutaneous sub-population in apoptosis and of the neuroprotective effects of NAC and ALCAR treatment on H(2)O(2)-challenged neurons.
    Experimental Brain Research 09/2012; 221(4):357-67. DOI:10.1007/s00221-012-3179-4 · 2.04 Impact Factor
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    ABSTRACT: Following the initial acute stage of spinal cord injury, a cascade of cellular and inflammatory responses will lead to progressive secondary damage of the nerve tissue surrounding the primary injury site. The degeneration is manifested by loss of neurons and glial cells, demyelination and cyst formation. Injury to the mammalian spinal cord results in nearly complete failure of the severed axons to regenerate. We have previously demonstrated that the antioxidants N-acetyl-cysteine (NAC) and acetyl-L-carnitine (ALC) can attenuate retrograde neuronal degeneration after peripheral nerve and ventral root injury. The present study evaluates the effects of NAC and ALC on neuronal survival, axonal sprouting and glial cell reactions after spinal cord injury in adult rats. Tibial motoneurons in the spinal cord were pre-labeled with fluorescent tracer Fast Blue one week before lumbar L5 hemisection. Continuous intrathecal infusion of NAC (2.4 mg/day) or ALC (0.9 mg/day) was initiated immediately after spinal injury using Alzet 2002 osmotic minipumps. Neuroprotective effects of treatment were assessed by counting surviving motoneurons and by using quantitative immunohistochemistry and Western blotting for neuronal and glial cell markers 4 weeks after hemisection. Spinal cord injury induced significant loss of tibial motoneurons in L4-L6 segments. Neuronal degeneration was associated with decreased immunostaining for microtubular-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker GFAP and microglial marker OX42 was increased. Treatment with NAC and ALC rescued approximately half of the motoneurons destined to die. In addition, antioxidants restored MAP2 and synaptophysin immunoreactivity. However, the perineuronal synaptophysin labeling was not recovered. Although both treatments promoted axonal sprouting, there was no effect on reactive astrocytes. In contrast, the microglial reaction was significantly attenuated. The results indicate a therapeutic potential for NAC and ALC in the early treatment of traumatic spinal cord injury.
    PLoS ONE 07/2012; 7(7):e41086. DOI:10.1371/journal.pone.0041086 · 3.23 Impact Factor
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    ABSTRACT: INTRODUCTION: Spinal cord injuries occur at an incidence of between 12.1- 57.8 per million worldwide and of these, 40-60% of the injuries occur at the cervical level [1] leading to significant morbidity and mortality. Spinal cord injuries cause an inflammatory response that leads to scarring at the site of injury, preventing regrowth of axons through the injury site. Therefore, therapies which could reduce the glial cell reaction around the injury zone may help recovery following spinal cord injury. We have previously shown that transplantation of rat bone marrow stem cells into injured spinal cord have neuroprotective and growth promoting effects and attenuate astrocyte and microglial cell reactivity [2]. Compared with bone marrow stem cells, adipose derived stem cells (ASC) are harvested relatively more easily, found in higher abundance, and proliferate more readily [3]. Therefore, in this study we have investigated the effect of human ASC in our spinal cord injury model. METHODS: Human ASC were isolated from abdominal fat tissue and expanded in vitro. Cultures were characterised using stem cell marker antibodies. RT-PCR was used to measure neurotrophic and angiogenic molecule expression. The ASC were injected in a rat spinal cord injury model. The spinal cord was transected through the lateral funiculus at the C3-C4 level unilaterally. Cells were injected 1mm cranial and caudal to the injury zone. Three weeks following injections, spinal cord tissue was harvested and analysed for human growth factor gene expression. At 8 weeks, tissue was harvested and the microglial and astrocyte cell reactions analysed by quantitative immunohistochemistry using OX-42 and GFAP antibodies respectively. RESULTS: Human ASC were positive for the general mesenchymal stem cell markers CD29 and CD54 and expressed fibronectin and type I collagen. The cell cultures were negative for haematopoietic cell markers CD14 and CD45. The cells could be efficiently differentiated along bone and fat cell lineages. In vitro, the cells expressed NGF, BDNF, NT-3, VEGF, IGF-1 and angiopoietin genes. Importantly, human mRNA transcripts were also detected in rats 3 weeks following spinal cord injury. At 8 weeks, analysis of immunohistochemistry showed a significant decrease in astrocytes and microglial cell reactivity in the rats injected with ASC. DISCUSSION & CONCLUSIONS: These preliminary results suggest that human adipose derived stem cells might provide some therapeutic effects following spinal cord injury. This needs to be further investigated with respect to effects on axonal regeneration and functional outcomes. REFERENCES: 1 M.J. DeVivo (2012) Epidemiology of traumatic spinal cord injur: trends and future implications Spinal Cord 1-8. 2 L.N. Novikova, M. Brohlin, P.J. Kingham, et al (2011) Neuroprotective and growth-promoting effects of bone marrow stromal cells after spinal cord injury in adult rats Cytotherapy 13: 873-887. 3 J.K. Fraser, I. Wulur, Z. Alfonso and M.H. Hedrick (2006) Fat tissue: an underappreciated source of stem cells for biotechnology TRENDS in Biotechnology 24:150- 155 ACKNOWLEDGEMENTS: This study was supported by the Swedish Medical Research Council, European Union, Umeå University, County of Västerbotten, Åke Wibergs Stiftelse, Magnus Bergvalls Stiftelse, Clas Groschinskys Minnesfond and the Gunvor and Josef Aner Foundation.
    Tissue and Cell Engineering Society, Liverpool; 07/2012
  • Kai-Hei Tse · Paul J Kingham · Lev N Novikov · Mikael Wiberg ·
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    ABSTRACT: Mesenchymal stem cells (MSCs) from adipose tissue and bone marrow are promising cell sources for autologous cell therapy of nerve injuries, as demonstrated by their intrinsic neurotrophic potential. However, extensive death of transplanted cells limits their full benefits. This study investigated the effects of ischaemia (metabolically induced by sodium azide and 2-deoxyglucose) and serum-derived mitogens on the viability and functional profile of MSCs in vitro. MSCs were more susceptible to combined, rather than individual, blockade of glycolysis and oxidative phosphorylation. Apoptosis and autophagy were involved in ischaemia-induced cell death. Chemical ischaemia alone and serum withdrawal alone induced a similar amount of cell death, with significantly different intracellular ATP maintenance. Combined ischaemia and serum deprivation had additive effects on cell death. Expression of the extracellular matrix (ECM) molecules laminin and fibronectin was attenuated under ischaemia and independent of serum level; however, BDNF and NGF levels remained relatively constant. Strong upregulation of VEGF and to a lesser extent angiopoietin-1 was observed under ischaemia but not in serum withdrawal conditions. Importantly, this study demonstrated similar reactions of MSCs derived from adipose and bone marrow tissue, in ischaemia-like and mitogen-deprived microenvironments in terms of viability, cellular energetics, cell death mechanisms and expression levels of various growth-promoting molecules. Also, the results suggest that ischaemia has a larger impact on the ability of MSCs to survive transplantation than withdrawal of mitogens.
    Journal of Tissue Engineering and Regenerative Medicine 06/2012; 6(6):473-85. DOI:10.1002/term.452 · 5.20 Impact Factor
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    ABSTRACT: Adult mesenchymal stem cells have self-renewal and multiple differentiation potentials, and play important roles in regenerative medicine. However, their use may be limited by senescence or age of the donor, leading to changes in stem cell functionality. We investigated morphological, molecular and functional differences between bone marrow-derived (MSC) and adipose-derived (ASC) stem cells isolated from neonatal, young and old rats compared to Schwann cells from the same animals. Immunocytochemistry, RT-PCR, proliferation assays, western blotting and transmission electron microscopy were used to investigate expression of senescence markers. Undifferentiated and differentiated ASC and MSC from animals of different ages expressed Notch-2 at similar levels; protein-38 and protein-53 were present in all groups of cells with a trend towards increased levels in cells from older animals compared to those from neonatal and young rats. Following co-culture with adult neuronal cells, dMSC and dASC from animals of all ages elicited robust neurite outgrowth. Mitotracker(®) staining was consistent with ultrastructural changes seen in the mitochondria of cells from old rats, indicative of senescence. In conclusion, this study showed that although the cells from aged animals expressed markers of senescence, aged MSC and ASC differentiated into SC-like cells still retain potential to support axon regeneration.
    Experimental Cell Research 05/2012; 318(16):2034-48. DOI:10.1016/j.yexcr.2012.05.008 · 3.25 Impact Factor
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    ABSTRACT: To address the need for the development of bioengineered replacement of a nerve graft, a novel two component fibrin glue conduit was combined with human mesenchymal stem cells (MSC) and immunosupressive treatment with cyclosporine A. The effects of MSC on axonal regeneration in the conduit and reaction of activated macrophages were investigated using sciatic nerve injury model. A 10mm gap in the sciatic nerve of a rat was created and repaired either with fibrin glue conduit containing diluted fibrin matrix or fibrin glue conduit containing fibrin matrix with MSC at concentration of 80×10(6) cells/ml. Cells were labeled with PKH26 prior to transplantation. The animals received daily injections of cyclosporine A. After 3 weeks the distance of regeneration and area occupied by regenerating axons and ED1 positives macrophages was measured. MSC survived in the conduit and enhanced axonal regeneration only when transplantation was combined with cyclosporine A treatment. Moreover, addition of cyclosporine A to the conduits with transplanted MSC significantly reduced the ED1 macrophage reaction.
    Neuroscience Letters 03/2012; 516(2):171-6. DOI:10.1016/j.neulet.2012.03.041 · 2.03 Impact Factor

Publication Stats

4k Citations
290.73 Total Impact Points


  • 1999-2014
    • Umeå University
      • • Department of Integrative Medical Biology (IMB)
      • • Department of Surgical and Perioperative Sciences
      Umeå, Västerbotten, Sweden
  • 2007-2009
    • Norrlands universitetssjukhus
      Umeå, Västerbotten, Sweden
    • The University of Manchester
      • Faculty of Life Sciences
      Manchester, England, United Kingdom
  • 2006-2008
    • St. James University
      Сент-Джеймс, New York, United States
  • 2002
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 1983-1999
    • Uppsala University
      • Department of Medical Cell Biology
      Uppsala, Uppsala, Sweden
  • 1989
    • Uppsala University Hospital
      • Section for Plastic Surgery
      Uppsala, Uppsala, Sweden