Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice

Department of Neurology, Henry Ford Health Sciences Center, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
Experimental Neurology (Impact Factor: 4.62). 10/2005; 195(1):16-26. DOI: 10.1016/j.expneurol.2005.03.018
Source: PubMed

ABSTRACT We investigated the treatment of remitting-relapsing experimental autoimmune encephalomyelitis (EAE) in mice with human bone marrow stromal cells (hBMSCs). hBMSCs were injected intravenously into EAE mice upon onset of paresis. Neurological functional tests were scored daily by grading clinical signs (score 0-5). Immunohistochemistry was performed to measure the transplanted hBMSCs, cell proliferation (bromodeoxyuridine, BrdU), oligodendrocyte progenitor cells (NG2), oligodendrocytes (RIP), and brain-derived neurotrophic factor (BDNF). The maximum clinical score and the average clinical scores were significantly decreased in the hBMSC-transplanted mice compared to the phosphate-buffered-saline-treated EAE controls, indicating a significant improvement in function. Demyelination significantly decreased, and BrdU(+) and BDNF(+) cells significantly increased in the hBMSC-treated mice compared to controls. Some BrdU(+) cells were colocalized with NG2(+) and RIP(+) immunostaining. hBMSCs also significantly reduced the numbers of vessels containing inflammatory cell infiltration. These data indicate that hBMSC treatment improved functional recovery after EAE in mice, possibly, via reducing inflammatory infiltrates and demyelination areas, stimulating oligodendrogenesis, and by elevating BDNF expression.

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    • "In contrast, mesenchymal stem cells (MSCs) isolated from many adult tissues have recently emerged as potent immunomodulatory cells with therapeutic applications in regenerative medicine (Phinney and Prockop, 2007) and in the treatment of inflammatory and autoimmune disorders (Uccelli and Prockop, 2010). Thus, MSCs derived from bone marrow and adipose tissue were shown to ameliorate experimental autoimmune encephalomyelitis and protected neurons from neuroinflammation in experimental models of brain ischemia and brain injury (Constantin et al., 2009; Uccelli et al., 2011; Zappia et al., 2005; Zhang et al. 2005). Among their multimodal actions, MSCs seem to modulate microglia activation (Kim et al., 2009; Zhou et al., 2009) although the mechanisms involved are largely unknown. "
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    ABSTRACT: Activated microglia play a central role in the course of neurodegenerative diseases as they secrete cytotoxic substances which lead to neuronal cell death. Understanding the mechanisms that drive activation of microglia is essential to reverse this phenotype and to protect from neurodegeneration. With some exceptions, evidence indicates that changes in cell morphology from a star shape to a round and flat shape accompany the process of activation in microglia. In this study, we investigated the effect of adipose-tissue-derived mesenchymal stem cells (ASCs), which exert important anti-inflammatory actions, in microglia morphology. Microglia exposed to ASCs or their secreted factors (conditioned medium) underwent a cell shape change into a ramifying morphology in basal and inflammatory conditions, similar to that observed in microglia found in healthy brain. Colony-stimulating factor-1 secreted by ASCs played a critical role in the induction of this phenotype. Importantly, ASCs reversed the activated round phenotype induced in microglia by bacterial endotoxins. The ramifying morphology of microglia induced by ASCs was associated with a decrease of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6, an increase in phagocytic activity, and the upregulation of neurotrophic factors and of Arginase-1, a marker for M2-like regulatory microglia. In addition, activation of the phosphoinositide-3-kinase/Akt pathway and the RhoGTPases Rac1 and Cdc42 played a major role in the acquisition of this phenotype. Therefore, these RhoGTPases emerge as key players in the ramification of microglia by anti-inflammatory agents like ASCs, being fundamental to maintain the tissue-surveying, central nervous system supporting state of microglia in healthy conditions. GLIA 2014.
    Glia 12/2014; 62(12). DOI:10.1002/glia.22714 · 6.03 Impact Factor
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    • "The muted in vivo efficacy of BM - MSCs that we observed is consistent with previous reports that showed only mild ( Gordon et al . , 2008 ; Zhang et al . , 2005 ) or negligible ( Payne et al . , 2013 ) effects in the EAE mouse model . Inter - estingly , BM - MSC#6 , the BM - MSC line that caused a modest reduction in EAE disease scores in the preonset model at passage 2 ( Figure 3C ) , failed to show any thera - peutic effects when used at passage 4 during the anti - iL - 6 antibody experiment "
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    ABSTRACT: Current therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stem cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS, yet the variability and low potency of MSCs from adult sources hinder their therapeutic potential. MSCs derived from human embryonic stem cells (hES-MSCs) may be better suited for clinical treatment of MS because of their unlimited and stable supply. Here, we show that hES-MSCs significantly reduce clinical symptoms and prevent neuronal demyelination in a mouse experimental autoimmune encephalitis (EAE) model of MS, and that the EAE disease-modifying effect of hES-MSCs is significantly greater than that of human bone-marrow-derived MSCs (BM-MSCs). Our evidence also suggests that increased IL-6 expression by BM-MSCs contributes to the reduced anti-EAE therapeutic activity of these cells. A distinct ability to extravasate and migrate into inflamed CNS tissues may also be associated with the robust therapeutic effects of hES-MSCs on EAE.
    Stem Cell Reports 07/2014; 3(1):1-16. DOI:10.1016/j.stemcr.2014.04.020
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    • "Mesenchymal stem cells also promote the appearance of regulatory T cells, inducing antigen-specific tolerance. Mesenchymal stem cell immunomodulatory potential has been recognized as the mechanism underlying the therapeutic effect observed in autoimmune diseases such as graft-versus-host disease, experimental encephalomyelitis and diabetes (Le Blanc et al. 2004; Zhang et al. 2005; Ezquer et al. 2012). In these pathological conditions, systemic administration of MSCs prevents the destruction of old and newly generated tissue cells. "
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    ABSTRACT: Diabetes mellitus is a complex metabolic disease that has become a global epidemic with more than 285 million cases worldwide. Major medical advances over the past decades have substantially improved its management, extending patients' survival. The latter is accompanied by an increased risk of developing chronic macro- and microvascular complications. Amongst them, diabetic retinopathy (DR) is the most common and frightening. Furthermore, during the past two decades, it has become the leading cause of visual loss. Irrespective of the type of diabetes, DR follows a well-known clinical and temporal course characterized by pericytes and neuronal cell loss, formation of acellular-occluded capillaries, occasional microaneurysms, increased leucostasis and thickening of the vascular basement membrane. These alterations progressively affect the integrity of retinal microvessels, leading to the breakdown of the blood-retinal barrier, widespread haemorrhage and neovascularization. Finally, tractional retinal detachment occurs leading to blindness. Nowadays, there is growing evidence that local inflammation and oxidative stress play pivotal roles in the pathogenesis of DR. Both processes have been associated with pericytes and neuronal degeneration observed early during DR progression. They may also be linked to sustained retinal vasculature damage that results in abnormal neovascularization. Currently, DR therapeutic options depend on highly invasive surgical procedures performed only at advanced stages of the disease, and which have proved to be ineffective to restore visual acuity. Therefore, the availability of less invasive and more effective strategies aimed to prevent or delay the onset of DR is highly desirable. Multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs), are promising healing agents as they contribute to tissue regeneration by pleiotropic mechanisms, with no evidence of significant adverse events. Here, we revise the pathophysiology of DR to identify therapeutic targets for donor MSCs. Also, we discuss whether an MSC-based therapy could prevent or delay the onset of DR.
    Acta ophthalmologica 06/2013; 92(2). DOI:10.1111/aos.12113 · 2.51 Impact Factor
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