Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis

Yang, Jingxian; Jiang, Zhilong; Fitzgerald, Denise; Ma, Cun‐Gen; Yu, Shuo; Li, Hongmei; Zhao, Zhao; Li, Yonghai; Ćirić, Bogoljub; Curtis, Mark; Rostami, Abdolmohamad; Zhang, Guang‐Xian

doi:10.1172/jci37914

Cited by 183 publications

(191 citation statements)

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“…The observed in vivo expression of IL-10 mRNA in the PP-lesioned T PLP mice may reflect that IL-10 can be produced by both T cells and microglia and macrophages and that production is enhanced by both cell types via T-cell interaction. 50 IL-10 has been associated with protection of oligodendrocytes in vitro 51 and promotion of remyelination in vivo, via either enhanced oligodendrogenesis 52 or enhanced clearance of myelin debris by microglia phagocytosis, 53 which was observed in the present study and in previous studies. 35 That we detected only low levels of IL-17 and IL-10 mRNA in the hippocampus of PP-lesioned T OVA mice despite the high levels detected in vitro likely reflects the low number of T cells detected in these animals or the lack of secondary activation by specific antigen recognition.…”

Section: Discussionsupporting

confidence: 63%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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In multiple sclerosis (MS), myelin-specific T cells are normally associated with destruction of myelin and axonal damage. However, in acute MS plaque, remyelination occurs concurrent with T-cell infiltration, which raises the question of whether T cells might stimulate myelin repair. We investigated the effect of myelin-specific T cells on oligodendrocyte formation at sites of axonal damage in the mouse hippocampal dentate gyrus. Infiltrating T cells specific for myelin proteolipid protein stimulated proliferation of chondroitin sulfate NG2-expressing oligodendrocyte precursor cells early after induction via axonal transection, resulting in a 25% increase in the numbers of oligodendrocytes. In contrast, T cells specific for ovalbumin did not stimulate the formation of new oligodendrocytes. In addition, infiltration of myelinspecific T cells enhanced the sprouting response of calretinergic associational/commissural fibers within the dentate gyrus. These results have implications for the perception of MS pathogenesis because they show that infiltrating myelin-specific T cells can stimulate oligodendrogenesis in the adult central nervous system. T cell infiltration, demyelination, and axonal damage are central pathologic features of multiple sclerosis (MS). Whereas the primary immune attack on oligodendrocytes and myelin is effected by T cells, 1,2 remyelination occurs in acute plaques, also in the presence of T cells. 3,4 Remyelination depends on chondroitin sulfate NG2-expressing adult oligodendrocyte precursor cells (OPCs). 5,6 OPCs retain the capacity to proliferate and differentiate into myelinating oligodendrocytes in response to toxic or inflammatory demyelination 7-9 and other forms of central nervous system (CNS) injury such as ischemia, 10 spinal cord injury, 11,12 axonal lesions, 13,14 and inflammation. 15 During differentiation, OPCs downregulate NG2 as cells acquire markers of mature oligodendrocytes such as 2=,3=-cyclic nucleotide 3=-phosphodiesterase (CNP). 16 The axonal damage that occurs within and distal to the acute MS lesion can be modeled in the hippocampal dentate gyrus by transection of the perforant pathway (PP), resulting in degeneration of the PP axons and their myelin sheaths in the outer part of the molecular layer. [17][18][19] PP lesions also induce proliferation of OPCs, which results in formation of new oligodendrocytes. 14 These newly formed oligodendrocytes are presumed to myelinate the axonal sprouts that extend from other afferent fiber systems in the dentate gyrus 20,21 such as the associational/commissural afferents from the calretinergic hilar mossy cells. 20,22,23 Indeed, in stratum radiatum of the hippocampal CA3 region, lesion-induced axonal sprouting is associated with formation of more oligodendrocytes and more myelin. 24 Because remyelination ultimately fails in MS, 25 it is assumed that autoimmune demyelination reduces the capacity for myelin repair. 26,27 We investigated the effect of myelin-specific T cells on the formation of oligodendrocytes in the dentate gyrus of ...

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Section: Discussionsupporting

confidence: 63%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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“…For example, IL-10 mRNA and protein expression by MSCs increased in response to HIϩMSC compared with HIϩVEH brain extracts. In an animal model of multiple sclerosis, administration of neural stem cells overexpressing IL-10 promoted remyelination (Yang et al, 2009). In neonatal brain damage, a similar mechanism might be operative since upregulation of IL-10 production by MSCs cultured with HIϩMSC brain extracts was associated with increased MBP staining after MSC3ϩ10 treatment.…”

Section: Discussionmentioning

confidence: 99%

Repeated Mesenchymal Stem Cell Treatment after Neonatal Hypoxia-Ischemia Has Distinct Effects on Formation and Maturation of New Neurons and Oligodendrocytes Leading to Restoration of Damage, Corticospinal Motor Tract Activity, and Sensorimotor Function

Velthoven¹,

Kavelaars²,

Bel³

et al. 2010

Journal of Neuroscience

173

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“…3,4) Neural stem cells (NSCs) are regarded as a promising source of donor cells in transplantation-based therapies for neurodegenerative disorders, which possess the capacity of self-renewal and production of a large number of newly generated cells that can differentiate into different neural cell types. [5][6][7] However, poor survival and limited neuronal differentiation of the transplanted NSCs in central nervous system (CNS) remain critical limitations for developing therapeutic strategies. 7,8) The adult CNS, especially the injured CNS, may provide a relatively non-permissive environment for engrafted NSCs.…”

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confidence: 99%

“…[5][6][7] However, poor survival and limited neuronal differentiation of the transplanted NSCs in central nervous system (CNS) remain critical limitations for developing therapeutic strategies. 7,8) The adult CNS, especially the injured CNS, may provide a relatively non-permissive environment for engrafted NSCs. 7,[9][10][11] Even under the best circumstances, the cell survival in injured CNS has been estimated to be near 10%, 12,13) and few cells differentiate into mature neuronal phenotypes.…”

mentioning

confidence: 99%

“…7,8) The adult CNS, especially the injured CNS, may provide a relatively non-permissive environment for engrafted NSCs. 7,[9][10][11] Even under the best circumstances, the cell survival in injured CNS has been estimated to be near 10%, 12,13) and few cells differentiate into mature neuronal phenotypes. 14,15) One of the most important reasons why those cells could not survive in the injured CNS is probably due to the sustained inflammation and oxidation in the disease areas.…”

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confidence: 99%

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The Coumarin Derivative Osthole Stimulates Adult Neural Stem Cells, Promotes Neurogenesis in the Hippocampus, and Ameliorates Cognitive Impairment in APP/PS1 Transgenic Mice

Kong

Yao

et al. 2015

Biological & Pharmaceutical Bulletin

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It is believed that neuronal death caused by abnormal deposition of amyloid-beta peptide is the major cause of the cognitive decline in Alzheimer's disease. Adult neurogenesis plays a key role in the rescue of impaired neurons and amelioration of cognitive impairment. In the present study, we demonstrated that osthole, a natural coumarin derivative, was capable of promoting neuronal stem cell (NSC) survival and inducing NSC proliferation in vitro. In osthole-treated APP/PS1 transgenic mice, a significant improvement in learning and memory function was seen, which was associated with a significant increase in the number of new neurons (Ki67 /NF-M ) and a decrease in apoptotic cells in the hippocampal region of the brain. These observations suggested that osthole promoted NSC proliferation, supported neurogenesis, and thus efficiently rescued impaired neurons in the hippocampus and ameliorated cognitive impairment. We also found that osthole treatment activated the Notch pathway and upregulated the expression of self-renewal genes Notch 1 and Hes 1 mRNA in NSCs. However, when Notch activity was blocked by the γ-secretase inhibitor DAPT, the augmentation of Notch 1 and Hes 1 protein was ameliorated, and the proliferation-inducing effect of osthole was abolished, suggesting that the effects of osthole are at least in part mediated by activation of the Notch pathway.

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Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis

Cited by 183 publications

References 60 publications

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Repeated Mesenchymal Stem Cell Treatment after Neonatal Hypoxia-Ischemia Has Distinct Effects on Formation and Maturation of New Neurons and Oligodendrocytes Leading to Restoration of Damage, Corticospinal Motor Tract Activity, and Sensorimotor Function

The Coumarin Derivative Osthole Stimulates Adult Neural Stem Cells, Promotes Neurogenesis in the Hippocampus, and Ameliorates Cognitive Impairment in APP/PS1 Transgenic Mice

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