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


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.

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Available from: Katia Mareschi, Oct 14, 2014
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    • "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. "
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    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.
    Stem Cell Research & Therapy 03/2014; 5(32). DOI:10.1186/scrt421 · 3.37 Impact Factor
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    • "In Nissl-stained sections, the nucleoli of spinal motor neurons in ventral horns were counted at 40X magnification. Only neurons with an area ≥ 80 μm2 and located in a position congruent with that of motor neuron groups were counted [28]. All ChAT+ profiles located in the ventral horns of immunoreacted sections clearly displaying a nucleolus on the plane of the section were counted. "
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    ABSTRACT: Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients.
    PLoS ONE 12/2013; 8(12):e82654. DOI:10.1371/journal.pone.0082654 · 3.23 Impact Factor
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    • "Moreover, in collagen-induced arthritis, hAd-MSCs reduced the prevalence and severity of the disease [16, 17]. The immunoregulatory function of human MSCs of various origin has been shown in many other animal models, including streptozotocin-induced diabetes [18], fulminant hepatic failure [19], amyotrophic lateral sclerosis [20], Parkinson's disease [21], systemic lupus erythematosus [22], and acute pancreatitis [23]. Such experiments are possible because MSCs are immune-tolerable, and human MSCs are capable of surviving for at least 8 weeks in immunocompetent mice [24]. "
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    ABSTRACT: Mesenchymal stem cells (MSCs) of human origin have been frequently applied to experimental animal models to evaluate their immunomodulatory functions. MSCs are known to be activated by cytokines from T cells, predominantly by interferon-γ (IFN-γ), in conjunction with other cytokines such as tumor necrosis factor-α (TNF-α) and interlukin-1β. Because IFN-γ is not cross-reactive between human and mouse species, the manner in which human MSCs administered in experimental animals are activated and stimulated to function has been questioned. In the present study, we established MSCs from human adipose tissue. They successfully suppressed the proliferation of not only human peripheral blood mononuclear cells but also mouse splenic T cells. When these human MSCs were stimulated with a culture supernatant of mouse T cells or recombinant murine TNF-α, they expressed cyclooxygenase-2 (COX-2), but not indoleamine 2,3-dioxygenase. The dominant role of COX-2 in suppressing mouse T cell proliferation was validated by the addition of COX-2 inhibitor in the co-culture, wherein the suppressed proliferation was almost completely recovered. In conclusion, human MSCs in a murine environment were activated, at least in part, by TNF-α and mainly used COX-2 as a tool for the suppression of in vitro T cell proliferation. These results should be considered when interpreting results for human MSCs in experimental animals.
    Anatomy & cell biology 12/2013; 46(4):262-71. DOI:10.5115/acb.2013.46.4.262
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