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Vasylovska, Svitlana
Publications (10 of 14) Show all publications
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
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
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
Kosykh, A., Ngamjariyawat, A., Vasylovska, S., König, N., Trolle, C., Lau, J., . . . N. Kozlova, E. (2015). Neural crest stem cells from hair follicles and boundary cap have different  effects on pancreatic islets in vitro. International Journal of Neuroscience, 125(7), 547-554
Open this publication in new window or tab >>Neural crest stem cells from hair follicles and boundary cap have different  effects on pancreatic islets in vitro
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2015 (English)In: International Journal of Neuroscience, ISSN 0020-7454, E-ISSN 1563-5279, Vol. 125, no 7, p. 547-554Article in journal (Refereed) Published
Abstract [en]

Purpose:

Neural crest stem cells derived from the boundary cap (bNCSCs), markedly promote survival, proliferation and function of insulin producing β-cells in vitro and in vivo after coculture/transplantation with pancreatic islets [ 1, 2 ]. Recently, we have shown that beneficial effects on β-cells require cadherin contacts between bNCSCs and β-cells [ 3, 4 ]. Here we investigated whether hair follicle (HF) NCSCs, a potential source for human allogeneic transplantation, exert similar positive effects on β-cells.

Materials and Methods:

We established cocultures of HF-NCSCs or bNCSCs from mice expressing enhanced green fluorescent protein together with pancreatic islets from DxRed expressing mice or NMRI mice and compared their migration towards islet cells and effect on proliferation of β-cells as well as intracellular relations between NCSCs and islets using qRT-PCR analysis and immunohistochemistry.

Results:

Whereas both types of NCSCs migrated extensively in the presence of islets, only bNCSCs demonstrated directed migration toward islets, induced β-cell proliferation and increased the presence of cadherin at the junctions between bNCSCs and β-cells. Even in direct contact between β-cells and HF-NCSCs, no cadherin expression was detected.

Conclusions:

These observations indicate that HF-NCSCs do not confer the same positive effect on β-cells as demonstrated for bNCSCs. Furthermore, these data suggest that induction of cadherin expression by HF-NCSCs may be useful for their ability to support β-cells in coculture and after transplantation.

Place, publisher, year, edition, pages
London: Informa Healthcare, 2015
Keywords
Diabetes, cell culture, coculture, intercellular contacts, migration
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-233149 (URN)10.3109/00207454.2014.950373 (DOI)000359884200011 ()25077520 (PubMedID)
Funder
Swedish Research Council, 20716
Note

De 2 första författarna delar förstaförfattarskapet

Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2018-01-11
Lau Börjesson, J., Vasylovska, S., Kozlova, E. N. & Carlsson, P.-O. (2015). Surface Coating of Pancreatic Islets With Neural Crest Stem Cells Improves Engraftment and Function After Intraportal Transplantation. Cell Transplantation, 24(11), 2263-2272
Open this publication in new window or tab >>Surface Coating of Pancreatic Islets With Neural Crest Stem Cells Improves Engraftment and Function After Intraportal Transplantation
2015 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 24, no 11, p. 2263-2272Article in journal (Refereed) Published
Abstract [en]

The present study aimed to develop techniques for surface coating of islets with neural crest stem cells (NCSCs) in order to enable cotransplantation to the clinically used liver site and then investigate engraftment and function intraportally of such bioengineered islets. Mouse islets were coated during incubation with enhanced green fluorescent protein (EGFP)-expressing mouse NCSCs and transplanted into the portal vein to cure diabetic mice. An intravenous glucose tolerance test was performed at 1 month posttransplantation. Islet grafts were retrieved and evaluated for vascular density, nerves, and glial cells. NCSCs expressed a vast number of key angiogenic and neurotrophic factors. Mice transplanted with NCSC-bioengineered islets responded better to the glucose load than recipient mice with control islets. NCSCs remained present in the vicinity or had often migrated into the NCSC-coated islets, and an improved islet graft reinnervation and revascularization was observed. Transplanted NCSCs differentiated into both glial and neural cells in the islet grafts. We conclude that bioengineering of islets with NCSCs for intraportal transplantation provides a possibility to improve islet engraftment and function. Pending successful establishment of protocols for expansion of NCSCs from, for example, human skin or bone marrow, this strategy may be applied to clinical islet transplantation.

Keywords
Islet transplantation, Stem cells, Neural progenitors, Engraftment, Revascularization, Reinnervation
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell Biology
Identifiers
urn:nbn:se:uu:diva-269293 (URN)10.3727/096368915X686184 (DOI)000364353300008 ()25581301 (PubMedID)
Funder
Swedish Research Council, 20716Swedish Research Council, 55X-15043Novo NordiskSwedish Diabetes AssociationSwedish Child Diabetes FoundationNovo NordiskAFA InsuranceSwedish Society of MedicineMagnus Bergvall Foundation
Available from: 2015-12-15 Created: 2015-12-15 Last updated: 2017-12-01Bibliographically approved
Trolle, C., Abrahamsson, N., König, N., Vasylovska, S. & Kozlova, E. (2014). Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents. BMC neuroscience (Online), 15, 60
Open this publication in new window or tab >>Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents
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2014 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, p. 60-Article in journal (Refereed) Published
Abstract [en]

The boundary cap is a transient group of neural crest-derived cells located at the presumptive dorsal root transitional zone (DRTZ) when sensory axons enter the spinal cord during development. Later, these cells migrate to dorsal root ganglia and differentiate into subtypes of sensory neurons and glia. After birth when the DRTZ is established, sensory axons are no longer able to enter the spinal cord. Here we explored the fate of mouse bNCSCs implanted to the uninjured DRTZ after dorsal root avulsion for their potential to assist sensory axon regeneration. Grafted cells showed extensive survival and differentiation after transplantation to the avulsed DRTZ. Transplanted cells located outside the spinal cord organized elongated tubes of Sox2/GFAP expressing cells closely associated with regenerating sensory axons or appeared as small clusters on the surface of the spinal cord. Others, migrating into the host spinal cordas single cells, differentiated to spinal cord neurons with different neurotransmitter characteristics, extensive fiber organization, and in some cases surrounded by glutamatergic terminal-like profiles. These findings demonstrate that bNCSCs implanted at the site of dorsal root avulsion injury display remarkable differentiation plasticity inside the spinal cord and in the peripheral compartment where they organize tubes associated with regenerating sensory fibers. These properties offer a basis for exploring the ability of bNCSCs to assist regeneration of sensory axons into the spinal cord and replace lost neurons in the injured spinal cord.

Place, publisher, year, edition, pages
BioMed Central, 2014
Keywords
neural stem cell, sensory neuron, spinal cord injury, cell differentiation, nerve regeneration, cell replacement
National Category
Neurosciences Neurology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-218685 (URN)10.1186/1471-2202-15-60 (DOI)000337318200001 ()
Funder
Swedish Research Council, 20716Swedish Research Council, 5420
Available from: 2014-02-14 Created: 2014-02-14 Last updated: 2018-01-11Bibliographically approved
Ngamjariyawat, A., Turpaev, K., Vasylovska, S., Kozlova, E. N. & Welsh, N. (2013). Co-Culture of Neural Crest Stem Cells (NCSC) and Insulin Producing Beta-TC6 Cells Results in Cadherin Junctions and Protection against Cytokine-Induced Beta-Cell Death. PLoS ONE, 8(4), e61828
Open this publication in new window or tab >>Co-Culture of Neural Crest Stem Cells (NCSC) and Insulin Producing Beta-TC6 Cells Results in Cadherin Junctions and Protection against Cytokine-Induced Beta-Cell Death
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, p. e61828-Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Transplantation of pancreatic islets to Type 1 diabetes patients is hampered by inflammatory reactions at the transplantation site leading to dysfunction and death of insulin producing beta-cells. Recently we have shown that co-transplantation of neural crest stem cells (NCSCs) together with the islet cells improves transplantation outcome. The aim of the present investigation was to describe in vitro interactions between NCSCs and insulin producing beta-TC6 cells that may mediate protection against cytokine-induced beta-cell death.

PROCEDURES: Beta-TC6 and NCSC cells were cultured either alone or together, and either with or without cell culture inserts. The cultures were then exposed to the pro-inflammatory cytokines IL-1β and IFN-γ for 48 hours followed by analysis of cell death rates (flow cytometry), nitrite production (Griess reagent), protein localization (immunofluorescence) and protein phosphorylation (flow cytometry).

RESULTS: We observed that beta-TC6 cells co-cultured with NCSCs were protected against cytokine-induced cell death, but not when separated by cell culture inserts. This occurred in parallel with (i) augmented production of nitrite from beta-TC6 cells, indicating that increased cell survival allows a sustained production of nitric oxide; (ii) NCSC-derived laminin production; (iii) decreased phospho-FAK staining in beta-TC6 cell focal adhesions, and (iv) decreased beta-TC6 cell phosphorylation of ERK(T202/Y204), FAK(Y397) and FAK(Y576). Furthermore, co-culture also resulted in cadherin and beta-catenin accumulations at the NCSC/beta-TC6 cell junctions. Finally, the gap junction inhibitor carbenoxolone did not affect cytokine-induced beta-cell death during co-culture with NCSCs.

CONCLUSION: In summary, direct contacts, but not soluble factors, promote improved beta-TC6 viability when co-cultured with NCSCs. We hypothesize that cadherin junctions between NCSC and beta-TC6 cells promote powerful signals that maintain beta-cell survival even though ERK and FAK signaling are suppressed. It may be that future strategies to improve islet transplantation outcome may benefit from attempts to increase beta-cell cadherin junctions to neighboring cells.

National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:uu:diva-198839 (URN)10.1371/journal.pone.0061828 (DOI)000317907200091 ()23613946 (PubMedID)
Funder
Swedish Research Council, 2010-11564-15-3Swedish Research Council, K2011-62X-20716-04-6
Available from: 2013-04-26 Created: 2013-04-26 Last updated: 2018-01-11Bibliographically approved
Grapensparr, L., Vasylovska, S., Olerud, J., Korsgren, O., Kozlova, E., Jansson, L. & Carlsson, P.-O. (2013). Neural Crest Stem Cells Induce Beta-cell Proliferation in Cultured and Transplanted Human Pancreatic Islets. Paper presented at 14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA. Transplantation, 96(6), S149-S149
Open this publication in new window or tab >>Neural Crest Stem Cells Induce Beta-cell Proliferation in Cultured and Transplanted Human Pancreatic Islets
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2013 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S149-S149Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-220750 (URN)000330443500270 ()
Conference
14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA
Available from: 2014-03-24 Created: 2014-03-20 Last updated: 2017-12-05Bibliographically approved
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