Article

Vercelli A, Mereuta OM, Garbossa D, Muraca G, Mareschi K, Rustichelli D et al. Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 31: 395-405

Department of Pediatrics, Regina Margherita Children's Hospital, University of Turin, Italy
Neurobiology of Disease (Impact Factor: 5.08). 07/2008; 31(3):395-405. DOI: 10.1016/j.nbd.2008.05.016

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a lethal disease affecting motoneurons. In familial ALS, patients bear mutations in the superoxide dismutase gene (SOD1). We transplanted human bone marrow mesenchymal stem cells (hMSCs) into the lumbar spinal cord of asymptomatic SOD1G93A mice, an experimental model of ALS. hMSCs were found in the spinal cord 10 weeks after, sometimes close to motoneurons and were rarely GFAP- or MAP2-positive. In females, where progression is slower than in males, astrogliosis and microglial activation were reduced and motoneuron counts with the optical fractionator were higher following transplantation. Motor tests (Rotarod, Paw Grip Endurance, neurological examination) were significantly improved in transplanted males. Therefore hMSCs are a good candidate for ALS cell therapy: they can survive and migrate after transplantation in the lumbar spinal cord, where they prevent astrogliosis and microglial activation and delay ALS-related decrease in the number of motoneurons, thus resulting in amelioration of the motor performance.

Download full-text

Full-text

Available from: Katia Mareschi, Oct 14, 2014
  • Source
    • "Stem cells possess self-renewal properties, and the ability to differentiate into different cell types, which may replace lost cells or specific neurons during epilepsy, such as inhibitory interneurons (Roper and Steindler, 2013). On the other hand, neuroprotective or antiinflammatory cytokines are released from stem cells, which are involved in the repair of autoimmune encephalomyelitis, amyotrophic lateral sclerosis, stroke and spinal cord injury (Einstein et al., 2007; Lin et al., 2011; Vercelli et al., 2008; Yang et al., 2008). To date, using stem cells to replace the cells that are lost during the course of epileptogenesis has been considered an effective strategy in the treatment of epilepsy (Cunningham et al., 2014; Hunt et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated the effects of intra-hippocampal transplantation of human umbilical mesenchymal stem cells (HUMSCs) on pilocarpine-treated rats. Sprague-Dawley rats were divided into the following three groups: (1) a normal group of rats receiving only PBS, (2) a status epilepticus (SE) group of rats with pilocarpine-induced SE and PBS injected into the hippocampi, and (3) a SE+HUMSC group of SE rats with HUMSC transplantation. Spontaneous recurrent motor seizures (SRMS) were monitored using simultaneous video and electroencephalographic recordings at two to four weeks after SE induction. The results showed that the number of SRMS within two to four weeks after SE was significantly decreased in SE+HUMSCs rats compared with SE rats. All of the rats were sacrificed on Day 29 after SE. Hippocampal morphology and volume were evaluated using Nissl staining and magnetic resonance imaging. The results showed that the volume of the dorsal hippocampus was smaller in SE rats compared with normal and SE+HUMSCs rats. The pyramidal neuron loss in CA1 and CA3 regions was more severe in the SE rats than in normal and SE+HUMSCs rats. No significant differences were found in the hippocampal neuronal loss or in the number of dentate GABAergic neurons between normal and SE+HUMSCs rats. Compared with the SE rats, the SE+HUMSCs rats exhibited a suppression of astrocyte activity and aberrant mossy fiber sprouting. Implanted HUMSCs survived in the hippocampus and released cytokines, including FGF-6, amphiregulin, glucocorticoid-induced tumor necrosis factors receptor (GITR), MIP-3β, and osteoprotegerin. In an in vitro study, exposure of cortical neurons to glutamate showed a significant decrease in cell viability, which was preventable by co-culturing with HUMSCs. Above all, the expression of human osteoprotegerin and amphiregulin were significantly increased in the media of the co-culture of neurons and HUMSCs. Our results demonstrate the therapeutic benefits of HUMSC transplantation for the development of epilepsy, which are likely due to the ability of the cells to produce neuroprotective and anti-inflammatory cytokines. Thus, HUMSC transplantation may be an effective therapy in the future.
    Preview · Article · Dec 2015 · Brain Behavior and Immunity
  • Source
    • "A number of animal studies have provided evidence that the transplantation of stem cells, including ESC, NPC, and MSC, through various routes make animal models live longer and restore functions, suggesting that these therapies may improve clinical outcomes1617181920212223. Adipose tissue-derived MSC (AdMSC) transplantation has shown to slow motor neuronal death and alleviate clinical manifestations and pathologies in mouse models through neuroprotection and immunomodulation[24]. Mainly, patientderived iPSC can be differentiated into motor neurons, enabling the autologous transplantation[25]. Results of cell-based therapy in animal models provide a rationale to imply that these approaches have the potential to have effects in human trials. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases are the hereditary and sporadic conditions which are characterized by progressive neuronal degeneration. Neurodegenerative diseases are emerging as the leading cause of death, disabilities, and a socioeconomic burden due to an increase in life expectancy. There are many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis, but we have no effective treatments or cures to halt the progression of any of these diseases. Stem cell-based therapy has become the alternative option to treat neurodegenerative diseases. There are several types of stem cells utilized; embryonic stem cells, induced pluripotent stem cells, and adult stem cell (mesenchymal stem cells and neural progenitor cells). In this review, we summarize recent advances in the treatments and the limitations of various stem cell technologies. Especially, we focus on clinical trials of stem cell therapies for major neurodegenerative diseases.
    Full-text · Article · Jan 2015
  • Source
    • "In the CNS, MSCs have been shown to migrate to areas of inflammation and reduce inflammation [47]. Several recent studies applying MSCs in experimental models of ALS have indicated attenuation of migroglial activation and reduction in reactive astrogliosis as potential mechanisms of improved clinical outcomes [21,48,49]. For these reasons, the immunomodulatory roles that MSCs play may be an added benefit of their use for cell therapy for ALS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the neuromuscular system and does not have a known singular cause. Genetic mutations, extracellular factors, non-neuronal support cells, and the immune system have all been shown to play varied roles in clinical and pathological disease progression. The therapeutic plasticity of mesenchymal stem cells (MSCs) may be well matched to this complex disease pathology, making MSCs strong candidates for cellular therapy in ALS. In this review, we summarize a variety of explored mechanisms by which MSCs play a role in ALS progression, including neuronal and non-neuronal cell replacement, trophic factor delivery, and modulation of the immune system. Currently relevant techniques for applying MSC therapy in ALS are discussed, focusing in particular on delivery route and cell source. We include examples from in vitro, preclinical, and clinical investigations to elucidate the remaining progress that must be made to understand and apply MSCs as a treatment for ALS.
    Full-text · Article · Mar 2014 · Stem Cell Research & Therapy
Show more