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

0508420 - ÚEM 2020 RIV US eng J - Journal Article
Řehořová, Monika - Vargová, Ingrid - Forostyak, Serhiy - Vacková, Irena - Turnovcová, Karolína - Skalníková, Helena - Vodička, Petr - Kubinová, Šárka - Syková, Eva - Jendelová, Pavla
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.
Stem Cells Translational Medicine. Roč. 8, č. 6 (2019), s. 535-547. ISSN 2157-6564. E-ISSN 2157-6580
R&D Projects: GA ČR(CZ) GA15-06958S; GA MŠMT(CZ) EF15_003/0000419
Institutional support: RVO:68378041 ; RVO:67985904
Keywords : amyotrophic lateral sclerosis * mesenchymal stem cells * necroptosis
OECD category: Neurosciences (including psychophysiology; Neurosciences (including psychophysiology (UZFG-Y)
Impact factor: 6.429, year: 2019
Method of publishing: Open access
https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.18-0223

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.
Permanent Link: http://hdl.handle.net/11104/0299332