Platelet-Derived Growth Factor Promotes Repair of Chronically Demyelinated White Matter

Vana, Adam C.; Flint, Nicole C.; Harwood, Norah E.; Le, Tai; Fruttiger, Marcus; Armstrong, Regina C.

doi:10.1097/nen.0b013e3181587d46

Cited by 92 publications

(70 citation statements)

References 54 publications

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“…Microglia have been recognized as a major source of IGF-1 (Lalancette-Hebert et al, 2007; Thored et al, 2009). In addition to IGF-1, BINCs expressed mRNAs encoding bFGF (Bethel et al, 1997), BMP2 (Gratacos et al, 2001), BMP4 (Niidome et al, 2008;Xin et al, 2006), BMP7 (Chang et al, 2003), GDNF (Kitagawa et al, 1999), HGF (Hayashi et al, 2001;Zhao et al, 2006), PDGF-A (Vana et al, 2007), and VEGF (Svensson et al, 2002), as shown by the quantitative real-time RT-PCR experiments in this study, and all of these factors have been shown to have neuroprotective effects through various mechanisms. BINCs were distinct from microglia or peritoneal macrophages in the expression patterns of each mRNA encoding these factors, suggesting that they are distinct cell types in spite of common expression of macrophage markers.…”

Section: Discussionmentioning

confidence: 99%

Iba1⁺/NG2⁺ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain

Smirkin

Matsumoto

Takahashi

et al. 2009

J Cereb Blood Flow Metab

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In a transient 90-min middle cerebral artery occlusion (MCAO) model of rats, a large ischemic lesion is formed where macrophage-like cells massively accumulate, many of which express a macrophage marker, Iba1, and an oligodendrocyte progenitor cell marker, NG2 chondroitin sulfate proteoglycan (NG2); therefore, the cells were termed BINCs (Brain Iba1 + /NG2 + Cells). A bone marrow transplantation experiment using green-fluorescent protein-transgenic rats showed that BINCs were derived from bone marrow. 5-Fluorouracil (5FU) injection at 2 days post reperfusion (2 dpr) markedly reduced the number of BINCs at 7 dpr, causing enlargement of necrotic volumes and frequent death of the rats. When isolated BINCs were transplanted into 5FU-aggravated ischemic lesion, the volume of the lesion was much reduced. Quantitative real-time RT-PCR showed that BINCs expressed mRNAs encoding bFGF, BMP2, BMP4, BMP7, GDNF, HGF, IGF-1, PDGF-A, and VEGF. In particular, BINCs expressed IGF-1 mRNA at a very high level. Immunohistochemical staining showed that IGF-1-expressing BINCs were found not only in rat but also human ischemic brain lesions. These results suggest that bone marrow-derived BINCs play a beneficial role in ischemic brain lesions, at least in part, through secretion of neuroprotective factors.

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Section: Discussionmentioning

confidence: 99%

Iba1⁺/NG2⁺ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain

Smirkin

Matsumoto

Takahashi

et al. 2009

J Cereb Blood Flow Metab

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“…Facilitation of remyelination was mediated by a graft-induced increase in host brain OPC proliferation. To demonstrate that, we took advantage of the fact that chronic cuprizone exposure (Mason et al, 2004;Vana et al, 2007) and the use of aged C57BL/6 mice (Shields et al, 1999;Sim et al, 2002;Shen et al, 2008) slows down the rate of spontaneous remyelination. Under these conditions we could examine the effect of NPC transplantation on the proliferation of host brain progenitor cells and on remyelination.…”

Section: Discussionmentioning

confidence: 99%

“…We therefore hypothesized that NPC transplantation may enhance the myelin regeneration capabilities of host brain cells. To this end we used the model of chronic cuprizone exposure which produces extensive demyelination (Mason et al, 2004;Vana et al, 2007) in aged mice, in which the rate of remyelination is slowed down (Shields et al, 1999;Sim et al, 2002;Shen et al, 2008). We show that intracerebroventricular (ICV) NPC transplantation induced a notable improvement in remyelination in cuprizone-treated mice.…”

Section: Introductionmentioning

confidence: 99%

Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration

Einstein¹,

Friedman-Levi²,

Grigoriadis³

et al. 2009

J. Neurosci.

112

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In multiple sclerosis lesions resident oligodendrocyte progenitor cells (OPCs) are present, but fail to remyelinate. In the current study we examined whether neural precursor cell (NPC) transplantation can facilitate host brain-derived remyelination. We used the chronic cuprizone-induced demyelination model in aged mice, in which slow remyelination follows cuprizone removal. NPCs were transplanted to the lateral ventricles (intracerebroventricular) of cuprizone-induced demyelinated brains. In this experimental setup, transplanted cells remained mostly in the periventricular area in an undifferentiated state. The extent of demyelination, remyelination, and proliferation of host brain regenerative cell population were examined at 1 week posttransplantation in the splenium of the corpus callosum, which was devoid of any transplanted cells. Transplantation of NPCs, but not of control, human embryonic kidney cells, significantly enhanced remyelination compared with sham-operated mice. Remyelination was performed exclusively by host brain OPCs. The proregenerative effect of transplanted NPCs was related to an increase in the proliferation of host brain OPCs. To examine the mechanism that underlies the proregenerative effect of NPCs in vitro, we used an NPC-OPC coculture system. These experiments indicated that NPCs induced the proliferation of OPCs and facilitated their differentiation into mature oligodendrocytes. The mitogenic effect of NPCs was mediated by platelet-derived growth factor-AA and fibroblast growth factor-2. In conclusion, NPC transplantation enhances hostderived myelin regeneration following chronic demyelination. This trophic effect may stimulate resident OPCs to overcome the remyelination failure in multiple sclerosis.

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“…One approach is to increase the recruitment and number of cycling OPCs by growth factor treatment. Candidates include platelet-derived growth factor [88][89][90], neuregulin-1, which is not essential for myelination in the CNS but can induce hypermyelination when overexpressed [91], and epidermal growth factor [59]. In addition, sonic hedgehog signaling stimulates the maintenance and renewal of neural precursors in the neurogenic niches of the adult brain [92,93].…”

Section: Myelin Regeneration Fails In Msmentioning

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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Platelet-Derived Growth Factor Promotes Repair of Chronically Demyelinated White Matter

Cited by 92 publications

References 54 publications

Iba1⁺/NG2⁺ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain

Iba1⁺/NG2⁺ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain

Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration

Cell Therapy for Multiple Sclerosis

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Platelet-Derived Growth Factor Promotes Repair of Chronically Demyelinated White Matter

Cited by 92 publications

References 54 publications

Iba1+/NG2+ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain

Iba1+/NG2+ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain

Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration

Cell Therapy for Multiple Sclerosis

Contact Info

Product

Resources

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Iba1⁺/NG2⁺ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain

Iba1⁺/NG2⁺ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain