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Kozlova, Elena
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Publications (10 of 32) Show all publications
Shteinfer-Kuzmine, A., Argueti, S., Gupta, R., Shvil, N., Abu-Hamad, S., Gropper, Y., . . . Israelson, A. (2019). A VDAC1-Derived N-Terminal Peptide Inhibits Mutant SOD1-VDAC1 Interactions and Toxicity in the SOD1 Model of ALS. Frontiers in Cellular Neuroscience, 13, Article ID 346.
Open this publication in new window or tab >>A VDAC1-Derived N-Terminal Peptide Inhibits Mutant SOD1-VDAC1 Interactions and Toxicity in the SOD1 Model of ALS
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2019 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 13, article id 346Article in journal (Refereed) Published
Abstract [en]

Mutations in superoxide dismutase (SOD1) are the second most common cause of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the death of motor neurons in the brain and spinal cord. SOD1 neurotoxicity has been attributed to aberrant accumulation of misfolded SOD1, which in its soluble form binds to intracellular organelles, such as mitochondria and ER, disrupting their functions. Here, we demonstrate that mutant SOD1 binds specifically to the N-terminal domain of the voltage-dependent anion channel (VDAC1), an outer mitochondrial membrane protein controlling cell energy, metabolic and survival pathways. Mutant SOD1(G93A) and SOD1(G85R), but not wild type SOD1, directly interact with VDAC1 and reduce its channel conductance. No such interaction with N-terminal-truncated VDAC1 occurs. Moreover, a VDAC1-derived N-terminal peptide inhibited mutant SOD1-induced toxicity. Incubation of motor neuron-like NSC-34 cells expressing mutant SOD1 or mouse embryonic stem cell-derived motor neurons with different VDAC1 N-terminal peptides resulted in enhanced cell survival. Taken together, our results establish a direct link between mutant SOD1 toxicity and the VDAC1 N-terminal domain and suggest that VDAC1 N-terminal peptides targeting mutant SOD1 provide potential new therapeutic strategies for ALS.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
ALS, misfolded SOD1, mutant SOD1, N-terminal peptide, VDAC1
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-393659 (URN)10.3389/fncel.2019.00346 (DOI)000480746900001 ()
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved
Mazzini, L., Ferrari, D., Andjus, P. R., Buzanska, L., Cantello, R., De Marchi, F., . . . Vescovi, A. L. (2018). Advances in stem cell therapy for amyotrophic lateral sclerosis. Expert Opinion on Biological Therapy, 18(8), 865-881
Open this publication in new window or tab >>Advances in stem cell therapy for amyotrophic lateral sclerosis
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2018 (English)In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 18, no 8, p. 865-881Article, review/survey (Refereed) Published
Abstract [en]

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies. Areas covered: This is an integrated review of pre-clinical and clinical studies focused on the development of cell-based therapies for ALS. We analyze the biology of stem cell treatments and results obtained from pre-clinical models of ALS and examine the methods and the results obtained to date from clinical trials. We discuss scientific, clinical, and ethical issues and propose some directions for future studies. Expert opinion: While data from individual studies are encouraging, stem-cell-based therapies do not yet represent a satisfactory, reliable clinical option. The field will critically benefit from the introduction of well-designed, randomized and reproducible, powered clinical trials. Comparative studies addressing key issues such as the nature, properties, and number of donor cells, the delivery mode and the selection of proper patient populations that may benefit the most from cell-based therapies are now of the essence. Multidisciplinary networks of experts should be established to empower effective translation of research into the clinic.

Keywords
Amyotrophic lateral sclerosis, stem cells, transplantation, clinical trials, animal models, cellular models
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-366394 (URN)10.1080/14712598.2018.1503248 (DOI)000445196000004 ()30025485 (PubMedID)
Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2018-11-22Bibliographically approved
Schizas, N., König, N., Andersson, B., Vasylovska, S., Hoeber, J., Kozlova, E. & Hailer, N. (2018). Neural crest stem cells protect spinal cord neurons from excitotoxic damage and inhibit glial activation by secretion of brain-derived neurotrophic factor. Cell and Tissue Research, 372(3), 493-505
Open this publication in new window or tab >>Neural crest stem cells protect spinal cord neurons from excitotoxic damage and inhibit glial activation by secretion of brain-derived neurotrophic factor
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2018 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 372, no 3, p. 493-505Article in journal (Refereed) Published
Abstract [en]

The acute phase of spinal cord injury is characterized by excitotoxic and inflammatory events that mediate extensive neuronal loss in the gray matter. Neural crest stem cells (NCSCs) can exert neuroprotective and anti-inflammatory effects that may be mediated by soluble factors. We therefore hypothesize that transplantation of NCSCs to acutely injured spinal cord slice cultures (SCSCs) can prevent neuronal loss after excitotoxic injury. NCSCs were applied onto SCSCs previously subjected to N-methyl-d-aspartate (NMDA)-induced injury. Immunohistochemistry and TUNEL staining were used to quantitatively study cell populations and apoptosis. Concentrations of neurotrophic factors were measured by ELISA. Migration and differentiation properties of NCSCs on SCSCs, laminin, or hyaluronic acid hydrogel were separately studied. NCSCs counteracted the loss of NeuN-positive neurons that was otherwise observed after NMDA-induced excitotoxicity, partly by inhibiting neuronal apoptosis. They also reduced activation of both microglial cells and astrocytes. The concentration of brain-derived neurotrophic factor (BDNF) was increased in supernatants from SCSCs cultured with NCSCs compared to SCSCs alone and BDNF alone mimicked the effects of NCSC application on SCSCs. NCSCs migrated superficially across the surface of SCSCs and showed no signs of neuronal or glial differentiation but preserved their expression of SOX2 and Krox20. In conclusion, NCSCs exert neuroprotective, anti-apoptotic and glia-inhibitory effects on excitotoxically injured spinal cord tissue, some of these effects mediated by secretion of BDNF. However, the investigated NCSCs seem not to undergo neuronal or glial differentiation in the short term since markers indicative of an undifferentiated state were expressed during the entire observation period.

Keywords
Neuroprotection, Suppressed glial activation, Excitotoxicity, Apoptosis, Secretion of soluble factors
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-356852 (URN)10.1007/s00441-018-2808-z (DOI)000432109000004 ()29516218 (PubMedID)
Funder
Swedish Research Council, 20716Stiftelsen Olle Engkvist Byggmästare
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2018-08-16Bibliographically approved
Hoeber, J., König, N., Trolle, C., Lekholm, E., Zhou, C., Pankratova, S., . . . Kozlova, E. (2017). A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord. Stem Cells and Development, 26(14), 1065-1077
Open this publication in new window or tab >>A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord
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2017 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 14, p. 1065-1077Article in journal (Refereed) Published
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.

Keywords
biomimetics, neural stem cells, spinal cord regeneration, stem cell transplantation
National Category
Neurosciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
Identifiers
urn:nbn:se:uu:diva-328587 (URN)10.1089/scd.2017.0019 (DOI)000405071200005 ()28562227 (PubMedID)
Funder
Stiftelsen Olle Engkvist ByggmästareSwedish Research Council, 20716
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-01-13Bibliographically approved
Trolle, C., Ivert, P., Hoeber, J., Rocamonde-Lago, I., Vasylovska, S., Lukanidin, E. & Kozlova, E. N. (2017). Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar. Regenerative Medicine, 12(4), 339-351
Open this publication in new window or tab >>Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar
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2017 (English)In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 12, no 4, p. 339-351Article in journal (Refereed) Published
Abstract [en]

AIM: During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury.

MATERIALS & METHODS: Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing.

RESULTS: hNPs and bNCSCs form similar gaps in the glial scar, but unlike hNPs, bNCSCs contribute Mts1/S100A4 (calcium-binding protein) expression to the scar and do not assist sensory axon regeneration.

CONCLUSION: bNCSC transplants contribute nonpermissive Mts1/S100A4-expressing cells to the glial scar after dorsal root avulsion.

Keywords
calcium-binding protein, glia, nerve degeneration, neural stem cell, sensory neuron, spinal cord
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-328589 (URN)10.2217/rme-2016-0163 (DOI)000406147100006 ()28621171 (PubMedID)
Funder
Swedish Research Council, 20716
Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-01-13Bibliographically approved
Aggarwal, T., Hoeber, J., Ivert, P., Vasylovska, S. & Kozlova, E. (2017). Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 14(3), 773-783
Open this publication in new window or tab >>Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons
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2017 (English)In: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, ISSN 1878-7479, Vol. 14, no 3, p. 773-783Article in journal (Refereed) Published
Abstract [en]

ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1(G93A)) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1(G93A) MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1(G93A) MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1(G93A) MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models.

Keywords
Amyotrophic lateral sclerosis, Neurodegeneration, Neuroglia, Oxidative stress, Transplantation
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-328588 (URN)10.1007/s13311-016-0505-8 (DOI)000405725300022 ()28070746 (PubMedID)
Funder
Swedish Research Council, 20716Stiftelsen Olle Engkvist Byggmästare
Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-09-07Bibliographically approved
König, N., Trolle, C., Kapuralin, K., Adameyko, I., Mitrecic, D., Aldskogius, H., . . . Kozlova, E. (2017). Murine neural crest stem cells and embryonic stem cell derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion. Journal of Tissue Engineering and Regenerative Medicine, 11(1), 129-137
Open this publication in new window or tab >>Murine neural crest stem cells and embryonic stem cell derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion
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2017 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 11, no 1, p. 129-137Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
sensory neuron, spinal cord, dorsal root transitional zone, regeneration, migration, glial cells, Schwann cells, motor neurons
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-218684 (URN)10.1002/term.1893 (DOI)000394173600012 ()24753366 (PubMedID)
Funder
Swedish Research Council, 20716
Available from: 2014-02-14 Created: 2014-02-14 Last updated: 2018-01-11Bibliographically approved
Wang, X., Xie, B., Qi, Y., Wallerman, O., Vasylovska, S., Andersson, L., . . . Welsh, N. (2016). Knock-down of ZBED6 in insulin-producing cells promotes N-cadherin junctions between beta-cells and neural crest stem cells in vitro. Scientific Reports, 6, Article ID 19006.
Open this publication in new window or tab >>Knock-down of ZBED6 in insulin-producing cells promotes N-cadherin junctions between beta-cells and neural crest stem cells in vitro
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 19006Article in journal (Refereed) Published
Abstract [en]

The role of the novel transcription factor ZBED6 for the adhesion/clustering of insulin-producing mouse MIN6 and βTC6 cells was investigated. Zbed6-silencing in the insulin producing cells resulted in increased three-dimensional cell-cell clustering and decreased adhesion to mouse laminin and human laminin 511. This was paralleled by a weaker focal adhesion kinase phosphorylation at laminin binding sites. Zbed6-silenced cells expressed less E-cadherin and more N-cadherin at cell-to-cell junctions. A strong ZBED6-binding site close to the N-cadherin gene transcription start site was observed. Three-dimensional clustering in Zbed6-silenced cells was prevented by an N-cadherin neutralizing antibody and by N-cadherin knockdown. Co-culture of neural crest stem cells (NCSCs) with Zbed6-silenced cells, but not with control cells, stimulated the outgrowth of NCSC processes. The cell-to-cell junctions between NCSCs and βTC6 cells stained more intensely for N-cadherin when Zbed6-silenced cells were co-cultured with NCSCs. We conclude that ZBED6 decreases the ratio between N- and E-cadherin. A lower N- to E-cadherin ratio may hamper the formation of three-dimensional beta-cell clusters and cell-to-cell junctions with NCSC, and instead promote efficient attachment to a laminin support and monolayer growth. Thus, by controlling beta-cell adhesion and cell-to-cell junctions, ZBED6 might play an important role in beta-cell differentiation, proliferation and survival.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-223614 (URN)10.1038/srep19006 (DOI)000368128900001 ()26750727 (PubMedID)
Funder
Swedish Diabetes AssociationSwedish Child Diabetes FoundationNovo NordiskSwedish Research Council, 20716Stiftelsen Olle Engkvist Byggmästare
Available from: 2014-04-22 Created: 2014-04-22 Last updated: 2018-01-11Bibliographically approved
Grapensparr, L., Vasylovska, S., Li, Z., Olerud, J., Jansson, L., Kozlova, E. & Carlsson, P.-O. (2015). Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth. Journal of Clinical Endocrinology and Metabolism, 100(4), E583-E590
Open this publication in new window or tab >>Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth
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2015 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. E583-E590Article in journal (Refereed) Published
Abstract [en]

Context: Neural crest stem cells (NCSCs) are capable of substantially improving murine islet function by promoting beta-cell proliferation. Objective: The present study aimed to investigate the potential of NCSCs to stimulate human beta-cell proliferation, and improve neural and vascular engraftment of human islets. Design, Setting, and Subjects: Human pancreatic islets from 18 brain-dead cadaveric donors (age range, 19-78 y) were obtained through the Nordic Network for Clinical Islet Transplantation. beta-cell proliferation and graft function was investigated at our experimental laboratory. Intervention and Main Outcome Measures: Human islets were transplanted, either alone or together with spheres of NCSCs. beta-cell proliferation, as well as islet neuralandvascular densities, were assessed by immunohistochemistry. Graft blood perfusion and oxygen tension were measured using laser-Doppler flowmetry and Clark microelectrodes, respectively. Results: Two days posttransplantation, the number of Ki67-positive beta-cells was doubled in human islets that had been exposed to NCSCs. Similar findings were obtained in vitro, as well as with EdU as proliferation marker. Four weeks posttransplantation, NCSC-exposed human islet grafts had much higher neural and vascular densities. The newly formed blood vessels were also functional, given that these human islets had a substantially higher blood perfusion and oxygen tension when compared with control transplants. Conclusion: We conclude that exposure to NCSCs stimulates human beta-cell proliferation, andthat these cells improve both the neural and vascular engraftment of transplanted human islets. NCSCs are a promising cellular therapy for translation into clinical use.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-253267 (URN)10.1210/jc.2014-4070 (DOI)000353361500009 ()25668197 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-25 Last updated: 2017-12-04Bibliographically approved
Hoeber, J., Trolle, C., König, N., Du, Z., Gallo, A., Hermans, E., . . . Kozlova, E. N. (2015). Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury. Scientific Reports, 5, Article ID 10666.
Open this publication in new window or tab >>Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10666Article in journal (Refereed) Published
Abstract [en]

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

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-251488 (URN)10.1038/srep10666 (DOI)000356063500001 ()26053681 (PubMedID)
Funder
Swedish Research Council, 5420, 20716
Available from: 2015-04-20 Created: 2015-04-20 Last updated: 2018-01-11Bibliographically approved
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