IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes

Hsieh, Jenny; Aimone, James B.; Kaspar, Brian K.; Kuwabara, Tomoko; Nakashima, Kinichi; Gage, Fred H.

doi:10.1083/jcb.200308101

Cited by 302 publications

(276 citation statements)

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“…We found upregulation of Pdgfa, Pdgfb, Vegfa, Vegfb, Tgfb1, Igf1, and Spp1, all of which have been reported to promote oligodendrocyte differentiation (Baumann and Pham-Dinh, 2001;Bradl and Lassmann, 2010;Chesik et al, 2008;Diemel et al, 2003;Frost et al, 2003;Hinks and Franklin, 1999;Hsieh et al, 2004;Kim et al, 2009;Selvaraju et al, 2004;Vela et al, 2002;Woodruff et al, 2004). Interestingly, we did not find upregulation of Gdnf or Fgf2, as reported by Gudi et al (2011).…”

Section: Discussionsupporting

confidence: 63%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

319

270

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In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

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Section: Discussionsupporting

confidence: 63%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

319

270

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“…29 and neuronal differentiation was induced as described in ref. 30. Briefly, neuronal precursors were isolated and placed in insulin-containing N2-supplemented (Invitrogen) DME:Ham's F-12 (Omega Scientific) medium containing 20 ng/mL FGF-2 (PeproTech, Inc.) and 20 ng/ml EGF (Peprotech, Inc.).…”

Section: Methodsmentioning

confidence: 99%

“…After 4 days, cells were fixed in 4% paraformaldehyde and immunostained for Tuj1 as described in ref. 30. In some cultures, 1 g/mL propidium iodide (Molecular Probes) or 1 g/mL Hoechst 22242 (Sigma) were added to label dead cells or all cells, respectively.…”

Section: Methodsmentioning

confidence: 99%

Histone deacetylases 1 and 2 control the progression of neural precursors to neurons during brain development

Montgomery¹,

Hsieh²,

Barbosa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The molecular mechanism by which neural progenitor cells commit to a specified lineage of the central nervous system remains unknown. We show that HDAC1 and HDAC2 redundantly control neuronal development and are required for neuronal specification. Mice lacking HDAC1 or HDAC2 in neuronal precursors show no overt histoarchitectural phenotypes, whereas deletion of both HDAC1 and HDAC2 in developing neurons results in severe hippocampal abnormalities, absence of cerebellar foliation, disorganization of cortical neurons, and lethality by postnatal day 7. These abnormalities in brain formation can be attributed to a failure of neuronal precursors to differentiate into mature neurons and to excessive cell death. These results reveal redundant and essential roles for HDAC1 and HDAC2 in the progression of neuronal precursors to mature neurons in vivo.cerebellum ͉ hippocampus ͉ neurogenesis ͉ neuronal precursors H istone acetyltransferases (HATs) and histone deacetylases (HDACs) provide the enzymatic basis for transcriptional activation and repression, respectively, through alterations of the chromatin landscape (1). Transcription factors recruit HDACs, either individually, or in repressive complexes to deacetylate lysine residues on histone tails, resulting in chromatin condensation and repression of gene expression (2). There are 4 classes of HDACs that coordinate proper gene regulation for numerous cellular processes: class I (HDAC1, -2, -3, and -8), class II (HDAC4, -5, -6, -7, -9, and -10), sirtuin class III, and class IV (HDAC11) (3). Although much has been learned through in vitro and inhibitor studies, little is known about the biological function of these individual enzymes in vivo (4). We have shown that the class I HDACs, HDAC1 and HDAC2, redundantly regulate cardiac growth and morphogenesis (5), however, the functions of HDAC1 and HDAC2 in other tissues remain unknown.HDAC inhibitors have shown significant potential for therapeutic use in a variety of disorders, including those of the central nervous system (CNS), such as neurodegenerative disease, motor neuron disease, and a number of other neurological disease states (6). Furthermore, it has been shown that HDAC inhibitors induce differentiation of both embryonic and adult cortical neuronal progenitor cells to neurons specifically (7-9). The wide expression pattern of a number of HDACs in the developing brain suggests specific roles for individual HDACs in neuronal development (10), however, the broad inhibition of classical HDAC inhibitors has precluded the analysis of individual HDACs pharmacologically. Additionally, the early lethality associated with global deletion of class I HDACs in knockout mice has compounded the difficulties in analyzing the functions of these enzymes during specific stages of neurogenesis in vivo (5, 11).To further investigate the specific roles of HDAC1 and HDAC2 in neuronal development, we generated conditional deletions of HDAC1 and HDAC2 in the central nervous system. Here, we show both HDAC1 and HDAC2 are required for multip...

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“…Different serotypes of adeno-associated vectors (AAV) also transduce sensory neurons in the dorsal root ganglia (DRG) through direct administration into the cerebral spinal fluid or via retrograde transport. [3][4][5][6] Specific transduction of non-neuronal cell types in the PNS, particularly of Schwann cells, may be of great interest for the treatment of hypo-or de-myelinating diseases, diabetic neuropathy or to overexpress trophic factors for nerve regeneration. Transduction with first-generation adenovirus showed a broad but transient tropism in many tissues, including different cell types in the PNS.…”

Section: Introductionmentioning

confidence: 99%

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

et al. 2011

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Efficient transduction of the peripheral nervous system (PNS) is required for gene therapy of acquired and inherited neuropathies, neuromuscular diseases and for pain treatment. We have characterized the tropism and transduction efficiency of different adeno-associated vectors (AAV) pseudotypes after sciatic nerve injection in the mouse. Among the pseudotypes tested, AAV2/1 transduced both Schwann cells and neurons, AAV2/2 infected only sensory neurons and AAV2/8 preferentially transduced Schwann cells. AAV2/8 expression in the sciatic nerve was detected up to 10 weeks after administration, the latest time point analyzed. The injected mice developed neutralizing antibodies against all AAVs tested; the titers were higher against AAV2/1 than AAV2/2 and were the lowest for AAV2/8, correlating with a higher transgene expression overtime. AAV2/8 coding for ciliary neurotrophic factor (CNTF) led to an upregulation of P0 and PMP22 myelin proteins, four weeks after transduction of injured sciatic nerves. Importantly, CNTF-transduced mice showed a significant increase in both GAP43 expression in sensory neurons, a marker of axonal regeneration, and the compound muscle action potential. These results prove the utility of AAV8 as a gene therapy vector for Schwann cells to treat myelin disorders or to improve nerve regeneration.

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IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes

Cited by 302 publications

References 50 publications

Identification of a microglia phenotype supportive of remyelination

Identification of a microglia phenotype supportive of remyelination

Histone deacetylases 1 and 2 control the progression of neural precursors to neurons during brain development

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

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