Transplanted neural precursor cells reduce brain inflammation to attenuate chronic experimental autoimmune encephalomyelitis

Einstein, Ofira; Grigoriadis, Nikolaos; Mizrachi-Kol, Rachel; Reinhartz, Etti; Polyzoidou, Eleni; Lavon, Iris; Milonas, Ioannis; Karussis, Dimitrios; Abramsky, Oded; Ben‐Hur, Tamir

doi:10.1016/j.expneurol.2005.11.007

Cited by 155 publications

(148 citation statements)

References 35 publications

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“…Indeed, NSCs express adhension molecules and chemokine receptors 10,41 and preferably migrated into inflamed sites of the CNS. 42 We have shown a comparable migration and distribution pattern of transplantaed SVZ-and BM-NSCs. However, these exogenous cells (GFP Figure 6A).…”

Section: Discussionmentioning

confidence: 75%

Evaluation of Bone Marrow- and Brain-Derived Neural Stem Cells in Therapy of Central Nervous System Autoimmunity

Yang

Yan

Ćirić

et al. 2010

The American Journal of Pathology

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease resulting from an autoimmune response against central nervous system (CNS) myelin. Inflammatory infiltration and demyelination of the CNS are hallmarks of MS and its animal model, experimental autoimmune encephalomyelitis (EAE).1-3 MS begins when peripherally activated myelin-reactive T cells infiltrate into the CNS, followed closely by other immune cells, including naïve myelin-reactive T cells, polyclonal T cells, macrophages, dendritic cells, B cells, and neutrophils.

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Section: Discussionmentioning

confidence: 75%

Evaluation of Bone Marrow- and Brain-Derived Neural Stem Cells in Therapy of Central Nervous System Autoimmunity

Yang

Yan

Ćirić

et al. 2010

The American Journal of Pathology

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“…Subsequently, the mice remain in a fixed neurological sequel, the severity of which is correlated with the extent of axonal loss [73]. 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].…”

Section: Immune Modulationmentioning

confidence: 99%

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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“…6 Transplantation of exogenous NSCs may be an effective therapeutic approach to accomplish remyelination in MS. A number of studies show that grafting NSCs does have a beneficial effect for the repair and reconstitution of brain tissues in EAE and other neurodegenerative disorders. [7][8][9] Yet, in most cases, NSCs alone had only mild to moderate efficacy in EAE, [9][10][11][12][13][14] and their beneficial effects were mainly by weak immunomodulatory and neuroprotective mechanisms. 6,9,13,[15][16][17] Concerns about the efficacy of NSC therapy for MS have been raised because of the likelihood that the hostile milieu generated by chronic inflammatory processes affects the migration and survival of the transplanted cells and inhibits their differentiation into remyelinating OLGs.…”

Section: Introductionmentioning

confidence: 99%

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

Zhang

Ćirić

et al. 2017

Molecular Therapy

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Inflammatory demyelination and axonal damage of the CNS are hallmarks of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Fingolimod (FTY720), the first FDA-approved oral medication for MS, suppresses acute disease but is less effective at the chronic stage, and whether it has a direct effect on neuroregeneration in MS and EAE remains unclear. Here we show that FTY720, at nanomolar concentrations, effectively protected survival of neural stem cells (NSCs) and enhanced their development into mature oligodendrocytes (OLGs) in vitro, primarily through the S1P3 and S1P5 receptors. In vivo, treatment with either FTY720 or NSCs alone had no effect on the secondary progressive stage of remitting-relapsing EAE, but a combination therapy with FTY720 and NSCs promoted significant recovery, including ameliorated clinical signs and CNS inflammatory demyelination, enhanced MBP synthesis and remyelination, inhibited axonal degeneration, and reduced astrogliosis. Moreover, FTY720 significantly improved incorporation and survival of transplanted NSCs in the CNS and drove their differentiation into more OLGs but fewer astrocytes, thus promoting remyelination and CNS repair processes in situ. Our data demonstrate a novel effect of FTY720 on NSC differentiation and remyelination, broadening its possible application to NSC-based therapy in the secondary progressive stage of MS.

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Transplanted neural precursor cells reduce brain inflammation to attenuate chronic experimental autoimmune encephalomyelitis

Cited by 155 publications

References 35 publications

Evaluation of Bone Marrow- and Brain-Derived Neural Stem Cells in Therapy of Central Nervous System Autoimmunity

Evaluation of Bone Marrow- and Brain-Derived Neural Stem Cells in Therapy of Central Nervous System Autoimmunity

Cell Therapy for Multiple Sclerosis

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

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