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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 ASEP 0508420 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title 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 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, ORCIDSource Title Stem Cells Translational Medicine. - : Oxford University Press - ISSN 2157-6564
Roč. 8, č. 6 (2019), s. 535-547Number of pages 13 s. Language eng - English Country US - United States Keywords amyotrophic lateral sclerosis ; mesenchymal stem cells ; necroptosis Subject RIV FH - Neurology OECD category Neurosciences (including psychophysiology Subject RIV - cooperation Institute of Animal Physiology and Genetics - Neurology R&D Projects GA15-06958S GA ČR - Czech Science Foundation (CSF) EF15_003/0000419 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UEM-P - RVO:68378041 ; UZFG-Y - RVO:67985904 UT WOS 000468215700004 EID SCOPUS 85062327988 DOI 10.1002/sctm.18-0223 Annotation An 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. Workplace Institute of Experimental Medicine Contact Lenka Koželská, lenka.kozelska@iem.cas.cz, Tel.: 241 062 218, 296 442 218 Year of Publishing 2020 Electronic address https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.18-0223
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