Human neural stem cells ameliorate autoimmune encephalomyelitis in non‐human primates

Pluchino, ﻿Stefano; Gritti, Angela; Blezer, Erwin L. A.; Amadio, Stefano; Brambilla, Elena; Borsellino, Giovanna; Cossetti, Chiara; Carro, Ubaldo Del; Comi, Giancarlo; Hart, Bert ‘t; Vescovi, Angelo L.; Martino, Gianvito

doi:10.1002/ana.21745

Cited by 189 publications

(200 citation statements)

References 42 publications

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“…NPC transplantation in MOG35-55-induced EAE mice attenuated brain inflammation, reduced acute and chronic axonal injury and demyelination, and improved the overall clinical and neurophysiological performance of the CNS of the mice [173,174]. Finally, such immune regulatory properties were also shown for human embryonic-stem cellderived NPCs in rodents [151] and for somatic NPCs in primates [175]. Again, the therapeutic effects of both these latter NPC sources was not related to graft-or host-driven remyelination, but rather were mediated by an immune regulatory mechanism that protected the CNS from immunemediated injury [151].…”

Section: Immune Modulationmentioning

confidence: 81%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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Section: Immune Modulationmentioning

confidence: 81%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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“…In vitro, both MSCs and NPCs are MHC-I low/medium and MHC-II negative (Klyushnenkova et al, 2005;Le Blanc et al, 2003;Pluchino et al, 2005Pluchino et al, , 2009a, but upregulation of MHC-I and -II expression is observed after long-term neurosphere expansion (Laguna Goya et al, 2011;Odeberg et al, 2005) or NPC exposure to proinflammatory cytokines such as interferon (IFN)-γ or tumor necrosis factor (TNF)-α (Johansson et al, 2008). Under basal growth conditions the co-stimulatory molecules CD80/ B7.1, CD86/B7.2 and CD40 are also absent in both MSCs and NPCs (Odeberg et al, 2005;Tse et al, 2003).…”

Section: In Vitro Stem Cell Immunogenicitymentioning

confidence: 99%

“…Human NPCs suppress the proliferation and alter the cytokine secretion profiles of xenogeneic (e.g. marmoset), antigen-specific and allogeneic mitogen-activated T cells (Kim et al, 2009b;Pluchino et al, 2009a). Compared with rodent NPCs, human NPCs have a lower cytotoxicity towards T cells, but a higher cytotoxicity toward monocyte/macrophages (Ricci-Vitiani et al, 2007) in vitro.…”

Section: Modulation Of Immune Responsesmentioning

confidence: 99%

How stem cells speak with host immune cells in inflammatory brain diseases

Pluchino

Cossetti

2013

Glia

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111

109

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Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases.

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“…38 In Coronel et al's study it is likely that the grafted MSCs exerted anti-nociceptive effects by either preventing injury-induced galanin upregulation with stimulation of pre-synaptic GAL2 receptors on primary afferents, or alternatively, stimulating GAL1 receptors. Other evidence supportive of the reparative immunological mechanisms in Franchi et al's study have shown that: the efficacy of transplanted NSCs in the treatment of neuropathic pain is mediated via neuroprotective and immunomodulatory mechanisms; 39 and that in a mouse model of spared nerve injury, intra-ventricular injection of human MSCs decreased mRNA levels of the proinflammatory IL-1 gene and suppressed activation of astrocytes and microglia, which was associated with a reduction in painlike behaviours. 40 The utility of intravenous systemic NSC administration in the treatment of neuropathic pain is further corroborated by evidence on the physiological mechanisms underlying NSC migration, namely, that NSCs cross the blood-brain barrier and enter the CNS where they modulate pain.…”

Section: Evidence On the Utility Of Adult Stem Cells For The Treatmenmentioning

confidence: 87%

Stem cell therapies for neuropathic pain

Seewoodhary

Harvey

2014

Br J Diabetes

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Neuropathic pain is a large-scale epidemiological problem affecting 13-26% of the diabetic population. The complex aetiology and pathophysiology coupled with the lack of a diagnostic test for the underlying cause renders the assessment of neuropathic pain subjective and the treatment difficult, especially as current licensed treatments are limited in their application towards the attainment of palliation.Cell therapies offer a novel curative therapeutic dimension for neuropathic pain. This is based on replacing damaged neuronal tissue, protecting against progressive nerve damage, and releasing soluble factors that act in a paracrine or endocrine manner, which facilitate repair and reversal of the pathology that underlies the genesis and propagation of damage within the somatosensory system. Cell therapies with potential utility for the treatment of neuropathic pain include embryonic stem cells, adult stem cells and induced pluripotent stem cells.

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Human neural stem cells ameliorate autoimmune encephalomyelitis in non‐human primates

Cited by 189 publications

References 42 publications

Cell Therapy for Multiple Sclerosis

Cell Therapy for Multiple Sclerosis

How stem cells speak with host immune cells in inflammatory brain diseases

Stem cell therapies for neuropathic pain

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