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.

• Keywords
• amyotrophic lateral sclerosis, biomaterials, cell therapy, conditioned medium, exosomes, mesenchymal stem cells, neurodegenerative diseases, spinal cord injury,
• Publication type
• Journal Article MeSH
• Review 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).

• Keywords
• ALS, iPS, motoneuron death, neurodegeneration, plasticity, proteoglycans, stem cells, transplantation,
• 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
• Names of Substances
• Nerve Growth Factors MeSH
• Apoptosis Regulatory Proteins MeSH
• Tenascin MeSH
• Versicans MeSH

Motor neurons (MN) degeneration is a main feature of amyotrophic lateral sclerosis (ALS), a neurological disorder with a progressive course. The diagnosis of ALS is essentially a clinical one. Most common symptoms include a gradual neurological deterioration that reflect the impairment and subsequent loss of muscle functions. Up-to-date ALS has no therapy that would prevent or cure a disease. Modern therapeutic strategies comprise of neuroprotective treatment focused on antiglutamatergic, antioxidant, antiapoptotic, and anti-inflammatory molecules. Stem cells application and gene therapy has provided researchers with a powerful tool for discovery of new mechanisms and therapeutic agents, as well as opened new perspectives for patients and family members. Here, we review latest progress made in basic, translational and clinical stem cell research related to the ALS. We overviewed results of preclinical and clinical studies employing cell-based therapy to treat neurodegenerative disorders. A special focus has been made on the neuroprotective properties of adult mesenchymal stromal cells (MSC) application into ALS patients. Finally, we overviewed latest progress in the field of embryonic and induced pluripotent stem cells used for the modeling and application during neurodegeneration in general and in ALS in particular.

• Keywords
• clinical trials, neurodegeneration, neuroprotection, stem cells,
• Publication type
• Journal Article MeSH
• Review MeSH

The transplantation of stem cells may have a therapeutic effect on the pathogenesis and progression of neurodegenerative disorders. In the present study, we transplanted human mesenchymal stem cells (MSCs) into the lateral ventricle of a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) at the age of eight months. We evaluated spatial reference and working memory after MSC treatment and the possible underlying mechanisms, such as the influence of transplanted MSCs on neurogenesis in the subventricular zone (SVZ) and the expression levels of a 56 kDa oligomer of amyloid β (Aβ*56), glutamine synthetase (GS) and glutamate transporters (Glutamate aspartate transporter (GLAST) and Glutamate transporter-1 (GLT-1)) in the entorhinal and prefrontal cortices and the hippocampus. At 14 months of age we observed the preservation of working memory in MSC-treated 3xTg-AD mice, suggesting that such preservation might be due to the protective effect of MSCs on GS levels and the considerable downregulation of Aβ*56 levels in the entorhinal cortex. These changes were observed six months after transplantation, accompanied by clusters of proliferating cells in the SVZ. Since the grafted cells did not survive for the whole experimental period, it is likely that the observed effects could have been transiently more pronounced at earlier time points than at six months after cell application.

• Keywords
• Alzheimer’s disease, Aβ*56, mesenchymal stem cells, neurogenesis, working memory,
• MeSH
• Alzheimer Disease pathology   physiopathology   therapy   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Maze Learning physiology   MeSH
• Glutamate-Ammonia Ligase metabolism   MeSH
• Memory, Short-Term physiology   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neurogenesis MeSH
• Cell Proliferation MeSH
• Mesenchymal Stem Cell Transplantation methods   MeSH
• Lateral Ventricles cytology   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amyloid beta-Peptides MeSH
• Glutamate-Ammonia Ligase MeSH

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder resulting in a lethal outcome. We studied changes in ventral horn perineuronal nets (PNNs) of superoxide dismutase 1 (SOD1) rats during the normal disease course and after the intrathecal application (5 × 10(5) cells) of human bone marrow mesenchymal stromal cells (MSCs) postsymptom manifestation. We found that MSCs ameliorated disease progression, significantly improved motor activity, and prolonged survival. For the first time, we report that SOD1 rats have an abnormal disorganized PNN structure around the spinal motoneurons and give different expression profiles of chondroitin sulfate proteoglycans (CSPGs), such as versican, aggrecan, and phosphacan, but not link protein-1. Additionally, SOD1 rats had different profiles for CSPG gene expression (Versican, Hapln1, Neurocan, and Tenascin-R), whereas Aggrecan and Brevican profiles remained unchanged. The application of MSCs preserved PNN structure, accompanied by better survival of motorneurons. We measured the concentration of cytokines (IL-1α, MCP-1, TNF-α, GM-CSF, IL-4, and IFN-γ) in the rats' cerebrospinal fluid and found significantly higher concentrations of IL-1α and MCP-1. Our results show that PNN and cytokine homeostasis are altered in the SOD1 rat model of ALS. These changes could potentially serve as biological markers for the diagnosis, assessment of treatment efficacy, and prognosis of ALS. We also show that the administration of human MSCs is a safe procedure that delays the loss of motor function and increases the overall survival of symptomatic ALS animals, by remodeling the recipients' pattern of gene expression and having neuroprotective and immunomodulatory effects.

• Keywords
• Extracellular matrix, Neurodegeneration, Preclinical trials, Proteoglycans, Stem cells,
• MeSH
• Amyotrophic Lateral Sclerosis metabolism   MeSH
• Cell Differentiation physiology   MeSH
• Chondroitin Sulfate Proteoglycans metabolism   MeSH
• Extracellular Matrix metabolism   MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor metabolism   MeSH
• Rats MeSH
• Mesenchymal Stem Cells cytology   MeSH
• Spinal Cord metabolism   MeSH
• Nerve Net cytology   MeSH
• Neurons cytology   MeSH
• Tumor Necrosis Factor-alpha metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Chondroitin Sulfate Proteoglycans MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor MeSH
• Tumor Necrosis Factor-alpha MeSH

BACKGROUND: A number of cardiovascular, neurological, musculoskeletal and other diseases have a limited capacity for repair and only a modest progress has been made in treatment of brain diseases. The discovery of stem cells has opened new possibilities for the treatment of these maladies, and cell therapy now stands at the cutting-edge of modern regenerative medicine and tissue engineering. Experimental data and the first clinical trials employing stem cells have shown their broad therapeutic potential and have brought hope to patients suffering from devastating pathologies of different organs and systems. AIMS: Here, we briefly review the main achievements and trends in cell-based therapy, with an emphasis on the main types of stem cells: embryonic, mesenchymal stromal and induced pluripotent cells. DISCUSSION: Many questions regarding the application of stem cells remain unanswered, particularly tumorigenicity, immune rejection and danger of gene manipulation. Currently, only MSC seems to be safe and might be considered to be a leading candidate for human application to treat pathologies that affect the cardiovascular, neurological and musculoskeletal systems.

• Keywords
• Clinical Trials, Embryonic Stem Cells, Induced Pluripotent Stem Cells, Mesenchymal Stromal Cells, PACS: 87.19.L-; 87.19.LW, Stem Cells,
• Publication type
• Journal Article MeSH

The transplantation of mesenchymal stem cells (MSC) is currently under study as a therapeutic approach for spinal cord injury, and the number of transplanted cells that reach the lesioned tissue is one of the critical parameters. In this study, intrathecally transplanted cells labeled with superparamagnetic iron oxide nanoparticles were guided by a magnetic field and successfully targeted near the lesion site in the rat spinal cord. Magnetic resonance imaging and histological analysis revealed significant differences in cell numbers and cell distribution near the lesion site under the magnet in comparison to control groups. The cell distribution correlated well with the calculated distribution of magnetic forces exerted on the transplanted cells in the subarachnoid space and lesion site. The kinetics of the cells' accumulation near the lesion site is described within the framework of a mathematical model that reveals those parameters critical for cell targeting and suggests ways to enhance the efficiency of magnetic cell delivery. In particular, we show that the targeting efficiency can be increased by using magnets that produce spatially modulated stray fields. Such magnetic systems with tunable geometric parameters may provide the additional level of control needed to enhance the efficiency of stem cell delivery in spinal cord injury.

• Keywords
• magnetism, mesenchymal stem cell, modeling, nanoparticle, spinal cord injury,
• MeSH
• Histocytochemistry MeSH
• Rats MeSH
• Magnetite Nanoparticles administration & dosage   chemistry   therapeutic use   MeSH
• Magnets * MeSH
• Mesenchymal Stem Cells chemistry   cytology   MeSH
• Spinal Cord chemistry   cytology   MeSH
• Spinal Cord Injuries surgery   MeSH
• Rats, Sprague-Dawley MeSH
• Injections, Spinal MeSH
• Models, Theoretical MeSH
• Mesenchymal Stem Cell Transplantation methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Magnetite Nanoparticles MeSH