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A Combination of Intrathecal and Intramuscular Application of Human Mesenchymal Stem Cells Partly Reduces the Activation of Necroptosis in the Spinal Cord of SOD1(G93A) Rats

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    SYSNO ASEP0508420
    Document TypeJ - Journal Article
    R&D Document TypeJournal Article
    Subsidiary JČlánek ve WOS
    TitleA Combination of Intrathecal and Intramuscular Application of Human Mesenchymal Stem Cells Partly Reduces the Activation of Necroptosis in the Spinal Cord of SOD1(G93A) Rats
    Author(s) Řehořová, Monika (UEM-P)
    Vargová, Ingrid (UEM-P) ORCID
    Forostyak, Serhiy (UEM-P) RID, ORCID
    Vacková, Irena (UEM-P)
    Turnovcová, Karolína (UEM-P) ORCID
    Skalníková, Helena (UZFG-Y) RID, ORCID
    Vodička, Petr (UZFG-Y) ORCID
    Kubinová, Šárka (UEM-P) RID, ORCID
    Syková, Eva (UEM-P) RID
    Jendelová, Pavla (UEM-P) RID, ORCID
    Source TitleStem Cells Translational Medicine. - : Oxford University Press - ISSN 2157-6564
    Roč. 8, č. 6 (2019), s. 535-547
    Number of pages13 s.
    Languageeng - English
    CountryUS - United States
    Keywordsamyotrophic lateral sclerosis ; mesenchymal stem cells ; necroptosis
    Subject RIVFH - Neurology
    OECD categoryNeurosciences (including psychophysiology
    Subject RIV - cooperationInstitute of Animal Physiology and Genetics - Neurology
    R&D ProjectsGA15-06958S GA ČR - Czech Science Foundation (CSF)
    EF15_003/0000419 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
    Method of publishingOpen access
    Institutional supportUEM-P - RVO:68378041 ; UZFG-Y - RVO:67985904
    UT WOS000468215700004
    EID SCOPUS85062327988
    DOI10.1002/sctm.18-0223
    AnnotationAn increasing number of studies have demonstrated the beneficial effects of human mesenchymal stem cells (hMSC) in the treatment of amyotrophic lateral sclerosis (ALS). We compared the effect of repeated intrathecal applications of hMSC or their conditioned medium (CondM) using lumbar puncture or injection into the muscle (quadriceps femoris), or a combination of both applications in symptomatic SOD1(G93A) rats. We further assessed the effect of the treatment on three major cell death pathways (necroptosis, apoptosis, and autophagy) in the spinal cord tissue. All the animals were behaviorally tested (grip strength test, Basso Beattie Bresnahan (BBB) test, and rotarod), and the tissue was analyzed immunohistochemically, by qPCR and Western blot. All symptomatic SOD1 rats treated with hMSC had a significantly increased lifespan, improved motor activity and reduced number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells. Moreover, a combined hMSC delivery increased motor neuron survival, maintained neuromuscular junctions in quadriceps femoris and substantially reduced the levels of proteins involved in necroptosis (Rip1, mixed lineage kinase-like protein, cl-casp8), apoptosis (cl-casp 9) and autophagy (beclin 1). Furthermore, astrogliosis and elevated levels of Connexin 43 were decreased after combined hMSC treatment. The repeated application of CondM, or intramuscular injections alone, improved motor aktivity, however, this improvement was not supported by changes at the molecular level. Our results provide new evidence that a combination of repeated intrathecal and intramuscular hMSC applications protects motor neurons and neuromuscular junctions, not only through a reduction of apoptosis and autophagy but also through the necroptosis pathway, which is significantly involved in cell death in rodent SOD1(G93A) model of ALS.
    WorkplaceInstitute of Experimental Medicine
    ContactLenka Koželská, lenka.kozelska@iem.cas.cz, Tel.: 241 062 218, 296 442 218
    Year of Publishing2020
    Electronic addresshttps://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.18-0223
Number of the records: 1  

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