Extracellular matrix (ECM) is a network of macromolecules which has two forms-perineuronal nets (PNNs) and a diffuse ECM (dECM)-both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan (HA) synthesis, we found downregulated staining for PNNs, HA, chondroitin sulfate proteoglycans, and glial fibrillary acidic protein. These changes were enhanced after 4 and 6 months and were reversible after a normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in the somatosensory cortex by 35%, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging revealed a decrease of mean diffusivity and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum, and spinal cord. This study shows the increase in ECS volume, a loss of FA, and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell-to-cell communication, and neural plasticity.

• MeSH
• Astrocytes metabolism   MeSH
• Chondroitin Sulfate Proteoglycans metabolism   MeSH
• Extracellular Matrix * metabolism   MeSH
• Extracellular Space * metabolism   MeSH
• Glial Fibrillary Acidic Protein metabolism   MeSH
• Hymecromone pharmacology   MeSH
• Rats MeSH
• Hyaluronic Acid MeSH
• Brain metabolism   MeSH
• Nerve Net drug effects   diagnostic imaging   MeSH
• Rats, Sprague-Dawley MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Autobiografie Evy Sykové, české neurofyzioložky, lékařky a političky, která obsahuje také rozhovor.; Kniha profesorky MUD. Evy Sykové, DrSc. mapuje osud ženy, která se musela v životě potýkat s mnoha překážkami a přesto, svou mimořádnou houževnatostí a pílí dosáhla toho, že se stala lékařkou, vědkyní, matkou a političkou.

• MeSH
• History, 20th Century MeSH
• History, 21st Century MeSH
• Physicians, Women history   MeSH
• Neurophysiology history   MeSH
• Politics MeSH
• Check Tag
• History, 20th Century MeSH
• History, 21st Century MeSH
• Publication type
• Autobiography MeSH
• Interview MeSH
• Geographicals
• Czech Republic MeSH
• Czechoslovakia MeSH

• Conspectus
• Lékařské vědy. Lékařství
• Biografie
• NML Fields
• neurovědy

• About
• Syková, Eva, 1944- Authority

[This corrects the article DOI: 10.3389/fcell.2021.695900.].

• Publication type
• Published Erratum MeSH

Preclinical and clinical studies with various stem cells, their secretomes, and extracellular vesicles (EVs) indicate their use as a promising strategy for the treatment of various diseases and tissue defects, including neurodegenerative diseases such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). Autologous and allogenic mesenchymal stem cells (MSCs) are so far the best candidates for use in regenerative medicine. Here we review the effects of the implantation of MSCs (progenitors of mesodermal origin) in animal models of SCI and ALS and in clinical studies. MSCs possess multilineage differentiation potential and are easily expandable in vitro. These cells, obtained from bone marrow (BM), adipose tissue, Wharton jelly, or even other tissues, have immunomodulatory and paracrine potential, releasing a number of cytokines and factors which inhibit the proliferation of T cells, B cells, and natural killer cells and modify dendritic cell activity. They are hypoimmunogenic, migrate toward lesion sites, induce better regeneration, preserve perineuronal nets, and stimulate neural plasticity. There is a wide use of MSC systemic application or MSCs seeded on scaffolds and tissue bridges made from various synthetic and natural biomaterials, including human decellularized extracellular matrix (ECM) or nanofibers. The positive effects of MSC implantation have been recorded in animals with SCI lesions and ALS. Moreover, promising effects of autologous as well as allogenic MSCs for the treatment of SCI and ALS were demonstrated in recent clinical studies.

• Publication type
• Journal Article MeSH
• Review MeSH

• MeSH
• COVID-19 MeSH

• MeSH
• COVID-19 MeSH

A promising therapeutic strategy for amyotrophic lateral sclerosis (ALS) treatment is stem cell therapy. Neural progenitors derived from induced pluripotent cells (NP-iPS) might rescue or replace dying motoneurons (MNs). However, the mechanisms responsible for the beneficial effect are not fully understood. The aim here was to investigate the mechanism by studying the effect of intraspinally injected NP-iPS into asymptomatic and early symptomatic superoxide dismutase (SOD)1G93A transgenic rats. Prior to transplantation, NP-iPS were characterized in vitro for their ability to differentiate into a neuronal phenotype. Motor functions were tested in all animals, and the tissue was analyzed by immunohistochemistry, qPCR, and Western blot. NP-iPS transplantation significantly preserved MNs, slowed disease progression, and extended the survival of all treated animals. The dysregulation of spinal chondroitin sulfate proteoglycans was observed in SOD1G93A rats at the terminal stage. NP-iPS application led to normalized host genes expression (versican, has-1, tenascin-R, ngf, igf-1, bdnf, bax, bcl-2, and casp-3) and the protection of perineuronal nets around the preserved MNs. In the host spinal cord, transplanted cells remained as progenitors, many in contact with MNs, but they did not differentiate. The findings suggest that NP-iPS demonstrate neuroprotective properties by regulating local gene expression and regulate plasticity by modulating the central nervous system (CNS) extracellular matrix such as perineuronal nets (PNNs).

• MeSH
• Amyotrophic Lateral Sclerosis therapy   MeSH
• Induced Pluripotent Stem Cells cytology   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Neural Stem Cells cytology   metabolism   transplantation   MeSH
• Neuronal Plasticity * MeSH
• Nerve Growth Factors genetics   metabolism   MeSH
• Peripheral Nerves physiology   MeSH
• Rats, Sprague-Dawley MeSH
• Apoptosis Regulatory Proteins genetics   metabolism   MeSH
• Nerve Regeneration MeSH
• Tenascin genetics   metabolism   MeSH
• Stem Cell Transplantation methods   MeSH
• Versicans genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

There is currently no treatment for restoring lost neurological function after stroke. A growing number of studies have highlighted the potential of stem cells. However, the mechanisms underlying their beneficial effect have yet to be explored in sufficient detail. In this study, we transplanted human induced pluripotent stem cell-derived neural precursors (iPSC-NPs) in rat temporary middle cerebral artery occlusion (MCAO) model. Using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) we monitored the effect of cells and assessed lesion volume and metabolite changes in the brain. We monitored concentration changes of myo-inositol (Ins), Taurine (Tau), Glycerophosphocholine+Phosphocholine (GPC+PCh), N-acetyl-aspartate+N-acetyl-aspartyl-glutamate (NAA+NAAG), Creatine+Phosphocreatine (Cr+PCr), and Glutamate+Glutamine (Glu+Gln) in the brains of control and iPSC-NP-transplanted rats. Based on initial lesion size, animals were divided into small lesion and big lesion groups. In the small lesion control group (SCL), lesion size after 4 months was three times smaller than initial measurements. In the small lesion iPSC-NP-treated group, lesion volume decreased after 1 month and then increased after 4 months. Although animals with small lesions significantly improved their motor skills after iPSC-NP transplantation, animals with big lesions showed no improvement. However, our MRI data demonstrate that in the big lesion iPSC-NP-treated (BTL) group, lesion size increased only up until 1 month after MCAO induction and then decreased. In contrast, in the big lesion control group, lesion size increased throughout the whole experiment. Significantly higher concentrations of Ins, Tau, GPC+PCh, NAA+NAAG, Cr+PCr, and Glu+Gln were found in in contralateral hemisphere in BTL animals 4 months after cell injection. Lesion volume decreased at this time point. Spectroscopic results of metabolite concentrations in lesion correlated with volumetric measurements of lesion, with the highest negative correlation observed for NAA+NAAG. Altogether, our results suggest that iPSC-NP transplantation decreases lesion volume and regulates metabolite concentrations within the normal range expected in healthy tissue. Further research into the ability of iPSC-NPs to differentiate into tissue-specific neurons and its effect on the long-term restoration of lesioned tissue is necessary.

• Publication type
• Journal Article MeSH

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 SOD1G93A 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 activity; 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 SOD1G93A model of ALS. Stem Cells Translational Medicine 2019;8:535-547.

• MeSH
• Amyotrophic Lateral Sclerosis therapy   MeSH
• Beclin-1 metabolism   MeSH
• Quadriceps Muscle cytology   metabolism   MeSH
• Longevity MeSH
• Injections, Intramuscular MeSH
• Caspase 9 metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Mesenchymal Stem Cells cytology   metabolism   MeSH
• Spinal Cord cytology   metabolism   MeSH
• Disease Models, Animal MeSH
• Motor Neurons metabolism   MeSH
• Necroptosis * MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Protein Serine-Threonine Kinases metabolism   MeSH
• Injections, Spinal MeSH
• Superoxide Dismutase-1 genetics   metabolism   MeSH
• Mesenchymal Stem Cell Transplantation * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The wide use of human multipotent mesenchymal stromal cells (MSCs) in clinical trials requires a full-scale safety and identity evaluation of the cellular product and subsequent transportation between research/medical centres. This necessitates the prolonged hypothermic storage of cells prior to application. The development of new, nontoxic, and efficient media, providing high viability and well-preserved therapeutic properties of MSCs during hypothermic storage, is highly relevant for a successful clinical outcome. In this study, a simple and effective trehalose-based solution was developed for the hypothermic storage of human bone marrow MSC suspensions for further clinical applications. Human bone marrow MSCs were stored at 4°C for 24, 48, and 72 hrs in the developed buffered trehalose solution and compared to several research and clinical grade media: Plasma-Lyte® 148, HypoThermosol® FRS, and Ringer's solution. After the storage, the preservation of viability, identity, and therapeutically associated properties of MSCs were assessed. The hypothermic storage of MSCs in the new buffered trehalose solution provided significantly higher MSC recovery rates and ability of cells for attachment and further proliferation, compared to Plasma-Lyte® 148 and Ringer's solution, and was comparable to research-grade HypoThermosol® FRS. There were no differences in the immunophenotype, osteogenic, and adipogenic differentiation and the immunomodulatory properties of MSCs after 72 hrs of cold storage in these solutions. The obtained results together with the confirmed therapeutic properties of trehalose previously described provide sufficient evidence that the developed trehalose medium can be applied as a low-cost and efficient solution for the hypothermic storage of MSC suspensions, with a high potential for translation into clinical practice.

• Publication type
• Journal Article MeSH