Maturation and electrophysiological properties of human pluripotent stem cell-derived oligodendrocytes.
- Authors
- Livesey, Matthew R; Magnani, Dario; Cleary, Elaine M; Vasistha, Navneet A; James, Owain T; Selvaraj, Bhuvaneish T; Burr, Karen; Story, David; Shaw, Christopher E; Kind, Peter C; Hardingham, Giles E; Wyllie, David J A; Chandran, Siddharthan
- Year
- 2016
- Journal
- Stem cells (Dayton, Ohio)
- PMID
- 26763608
- DOI
- 10.1002/stem.2273
- PMCID
- PMC4840312
Rodent-based studies have shown that the membrane properties of oligodendrocytes play prominent roles in their physiology and shift markedly during their maturation from the oligodendrocyte precursor cell (OPC) stage. However, the conservation of these properties and maturation processes in human oligodendrocytes remains unknown, despite their dysfunction being implicated in human neurodegenerative diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Here, we have defined the membrane properties of human oligodendrocytes derived from pluripotent stem cells as they mature from the OPC stage, and have identified strong conservation of maturation-specific physiological characteristics reported in rodent systems. We find that as human oligodendrocytes develop and express maturation markers, they exhibit a progressive decrease in voltage-gated sodium and potassium channels and a loss of tetrodotoxin-sensitive spiking activity. Concomitant with this is an increase in inwardly rectifying potassium channel activity, as well as a characteristic switch in AMPA receptor composition. All these steps mirror the developmental trajectory observed in rodent systems. Oligodendrocytes derived from mutant C9ORF72-carryng ALS patient induced pluripotent stem cells did not exhibit impairment to maturation and maintain viability with respect to control lines despite the presence of RNA foci, suggesting that maturation defects may not be a primary feature of this mutation. Thus, we have established that the development of human oligodendroglia membrane properties closely resemble those found in rodent cells and have generated a platform to enable the impact of human neurodegenerative disease-causing mutations on oligodendrocyte maturation to be studied.
Derivation and specification of oligodendrocytes from human pluripotent stem cell (hPSC)‐derived oligodendrocyte precursor cells (OPCs). (A): Summary of the protocol used to generate hPSC‐derived oligodendrocytes: (1) hPSCs were neuralized via dual‐SMAD inhibition. (2) NPCs were patterned to ventral spinal cord by exposure to retinoic acid and sonic hedgehog agonists, purmorphamine, and SAG. (3) spinal cord‐patterned NPCs were converted to OPCs by exposure to PDGFα and other mitogens. (4) OPCs could be further expanded by mechanical dissociation. (5) Oligodendrocyte differentiation was induced by mitogen withdrawal. (B): Representative staining of cells 1 week post‐mitogen removal identifies OLIG2+‐progenitors, and cells expressing PDGFRα, O4, and MBP in all lines examined. Scale bar = 50 μm. (C): Percentage of PDGFRα+‐cells (ES/iPS1/iPS2: N = 4/4/3) and (D) O4+‐cells (ES/iPS1/iPS2: N = 4/13/13) in week 1 cultures. (E): Percentage O4+‐cells that express PDGFRα(ES/iPS1/iPS2: N = 4/4/3) and MBP (ES/iPS1/iPS2: N = 4/5/6). Equivalent cellular specification was observed across all lines. (F): Example images illustrating no overlap of PDGFRα+‐ and O4+‐cells (upper panels) but substantial overlap of MBP+‐ and O4+‐cells (lower panels). Scale bar = 12 μm. (G): Sholl analysis performed upon week 1 and 3 O4+‐oligodendrocytes. Abbreviations: DAPI, 4',6‐diamidino‐2‐phenylindole; ES, embryonic stem cell; FGF, fibroblast growth factor; hPSC, human pluripotent stem cell; IGF, Insulin‐like growth factor; iPS, induced pluripotent stem cell; MBP, myelin basic protein; NPC, neural precursor cell; OL, oligodendrocyte; OPC, oligodendrocyte precursor cell; PDGF, platelet‐derived growth factor; RA, retinoic acid; SAG, smoothened agonist; scNPC, spinal cord‐patterned neural precursor.
Membrane current properties of human pluripotent stem cell‐derived oligodendrocyte precursor cells (OPCs) and oligodendrocytes. (A): Whole‐cell current recordings from a PDGFRα+‐OPC (blue) and week 3 O4+‐oligodendrocyte (orange) in response to a voltage‐step protocol that involved incremental application of 20 mV voltage steps from a holding potential of –84 mV. Live‐stained cells are shown inset. (B): Mean normalized current–voltage plots for PDGFRα+‐OPCs, week 1 (circles) and week 3 (triangles) O4+‐oligodendrocytes (n = 9–17, N = 3–6) derived from the ES line. Current amplitudes were measured 175 milliseconds after voltage‐step initiation and normalized to –64 mV current data. (C): Mean PDGFRα+‐OPC (iPS1/iPS2: n = 10/5, N = 3/1) and week 3 O4+‐oligodendrocyte (iPS1/iPS2: n = 8/6, N = 4/2) rectification index data calculated for each line examined. (D): Mean input resistance measurements for PDGFRα+‐OPCs (ES/iPS1/iPS2: n = 20/21/8, N = 3/3/3) and O4+‐oligodendrocytes (ES/iPS1/iPS2: n = 26‐32/19/7, N = 3/3/3). (E): Mean whole‐cell capacitance measurements for PDGFRα+‐OPCs (ES/iPS1/iPS2: n = 22/21/12, N = 3/3/3) and O4+‐oligodendrocytes (ES/iPS1/iPS2: n = 32‐41/26/7, N = 3/3/3). *, p < 0.05; **, p < 0.01, ***, p < 0.001, respectively. Abbreviations: ES, embryonic stem cell; iPS, induced pluripotent stem cell; PDGFRα, platelet‐derived growth factor receptor alpha.
Voltage‐gated Na+‐channel expression in human pluripotent stem cell‐derived oligodendrocyte precursor cells (OPCs) and oligodendrocytes. (A): Current‐clamp recording demonstrating that PDGFRα+‐OPCs exhibited tetrodotoxin (TTX)‐sensitive spikes in response to depolarization by current injection (each current step below trace represents 10 pA). (B): To isolate and measure Na V‐channel activity, the membrane potential was initially stepped in 20 mV increments from –84 mV to + 16 mV (activation). Scale bars = 500 pA, 5 milliseconds. The protocol was then repeated in the presence of TTX and the current data subtracted from that of the former to yield the TTX‐sensitive Na V‐specific current. Not all TTX‐sensitive currents are shown for figure clarity. (C): Normalized current–voltage plot of Na V‐channel activity expressed by PDGFRα+‐OPCs. Data were normalized to +16 mV current data. (D): Decrease in Na V‐channel expression from PDGFRα+‐OPCs to O4+‐oligodendrocytes (n = 5–18, N = 3; Mann Whitney U tests). ***, p < 0.001. Abbreviations: PDGFRα, platelet‐derived growth factor receptor alpha; TTX, tetrodotoxin.
Voltage‐gated K+‐channel expression in human pluripotent stem cell‐derived oligodendroglia. (A): To isolate I k‐channel activity, 10 mV incremental voltage‐pulses were initially applied to activate I k‐channels in the presence of tetrodotoxin (TTX) (activation). This was then repeated in the presence of TEA and the current data subtracted from that of the former to determine the I K‐specific current (subtracted). I K‐current amplitudes were measured 200 milliseconds after activation. The examples shown are from PDGFRα+‐oligodendrocyte precursor cells (OPCs). (B): Normalized current–voltage plot of I K‐channel activity measured from PDGFRα+‐OPCs (n = 4) and O4+‐oligodendrocytes (n = 4). Data were normalized to +46 mV current data. (C): Decrease in I K‐channel expression from PDGFRα+‐OPCs to O4+‐oligodendrocytes (n = 8–15, N = 3‐4). Current amplitude data were measured from the 100‐mV step. (D): I A‐channel activity was measured in the presence of TTX and Cd2+ (100 μM). The holding potential was pre‐stepped to –124 mV (500 milliseconds) and, there from, the holding potential depolarized in 10 mV increments before returning to –84 mV (activation). Since I A‐channels inactivate rapidly upon depolarization, an inactivation protocol pre‐stepped cells to –34 mV from –84 mV to isolate non‐I A current (inactivation), which was subtracted from the former to generate the I A‐mediated current (subtracted). I A‐current amplitudes were measured from the transient peak responses. The examples shown are from PDGFRα+‐OPCs. (E): Normalized current–voltage plot of I A‐channel activity measured from PDGFRα+‐OPCs (n = 6) and O4+‐oligodendrocytes (n = 4). Data were normalized to +36 mV current data. (F): Decrease in I A‐channel expression from PDGFRα+‐OPCs to O4+‐oligodendrocytes (n = 6‐12, N = 3‐4). Current amplitude data were measured from the depolarization step to +16 mV. *, p < 0.05; ***, p < 0.001. Abbreviations: PDGFRα, platelet‐derived growth factor receptor alpha; TEA, tetraethyl ammonium.
Inwardly rectifying K+‐channel expression in human pluripotent stem cell‐derived oligodendrocyte precursor cells (OPCs) and oligodendrocytes. (A): Representative images of K ir4.1 subunit immunostaining in PDGFRα+‐OPCs (arrowhead), and O4+‐ (arrow) and MBP+‐oligodendrocytes. Scale bar = 30 μm. (B): K ir‐channel measurements were performed using an extracellular solution in which KCl (50 mM) replaced an equimolar amount of NaCl. To isolate of K ir‐channel activity initially 10 mV incremental voltage‐steps were applied in the range –134 mV to + 6 mV from a holding potential of –74 mV and then repeated in the presence of Ba2+ (1 mM). Note that only selected voltage‐step current recordings are shown in the figure for clarity. Leak‐subtraction of K ir‐channel current data were performed using the pre‐pulse current amplitude in the presence of Ba2+ as zero current. It was not possible to extract a current–voltage (I‐V) plot from PDGFRα+‐cells given the very low K ir channel current amplitudes. Scale bars = 100 pA, 50 milliseconds. (C): Normalized I‐V of K ir‐channel activity obtained from O4+‐oligodendrocytes (n = 7). Data were normalized to –114 mV current data. (D): An increase in mean K ir‐channel expression in week 3 O4+‐oligodendrocytes (n = 8, N = 3) from that of week 1 O4+‐oligodendrocytes (n = 10, N = 2) and PDGFRα+‐OPCs (n = 9, N = 3). Current amplitude data were measured from the depolarization step to –134 mV. Note that the increase in current density also factors the whole‐cell capacitance. (E): The mean resting membrane potential PDGFRα+‐OPCs (n = 19, N = 3), week 1 O4+‐oligodendrocytes (n = 29, N = 7) and week 3 O4+‐oligodendrocytes (n = 20, N = 4). Error bars are obscured by the mean data point. *, p < 0.05; **, p < 0.01, respectively. Abbreviations: PDGFRα, platelet‐derived growth factor receptor alpha; RMP, resting membrane potential.
AMPA receptors in human pluripotent stem cell (hPSC)‐derived oligodendrocyte precursor cells (OPCs) and oligodendrocytes. (A): AMPA‐mediated whole‐cell current responses in a PDGFRα+‐OPC are strongly potentiated by cyclothiazide and blocked by CNQX. (B): Depicts sample recordings in which responses to applications of GABA (100 μM), NMDA (100 μM, in the presence of glycine [50 μM]) were obtained from week 3 O4+‐oligodendrocytes. (C): Mean current densities for AMPA (n = 10/7/11, N = 2/1/2), NMDA (n = 6/8, N = 2/2), and GABA responses (n = 8/19, N = 3/3). (D): Mean normalized mRNA fold expression data for AMPAR subunits GluA1‐GluA4 in OPC cultures (N = 3) and week 3 O4+‐oligodendrocytes (N = 13) as assessed by quantitative real‐time polymerase chain reaction. Data were normalized to GluA1 for each maturation stage after normalizing to β‐actin and GAPDH. (E): Sample nonstationary fluctuation analysis recordings of AMPAR‐mediated currents from a PDGFRα+‐OPC and, (F) week 3 O4+‐oligodendrocyte. (G): Plot describing the linear relationship of the variance of the AC‐coupled current to the DC‐current amplitude for the former recordings in c and d. The fitted slopes for each plot gave respective unitary single‐channel current amplitude estimates of −0.45 pA and −0.1 pA, respectively, from which the unitary conductance was calculated. (H): Mean AMPAR conductance for PDGFRα+‐OPCs and O4+‐oligodendrocytes derived from control hPSC lines. (I): Example recording of 1‐naphthyl acetyl spermine (NASPM) block of steady‐state currents evoked by AMPA in a PDGFRα+‐OPC and, (J) week 3 O4+‐oligodendrocyte. (K): Mean percentage block of AMPA currents by NASPM. *, p < 0.05; **, p < 0.01; ***, p < 0.001, respectively. Abbreviations: AMPA, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid; CNQX, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione; CTZ, cyclothiazide; GABA, gamma‐aminobutyric acid; NASPM, 1‐naphthyl acetyl spermine; NMDA, N‐methyl‐D‐aspartate; PDGFRα, platelet‐derived growth factor receptor alpha.
Oligodendrocytes derived from mutant C9ORF72 patients. (A): Representative staining of iPSC91 and iPSC92 cells 1 week post‐mitogen removal identifies OLIG2+‐progenitors, and cells expressing PDGFRα, O4, and MBP. Scale bar = 50 μm. (B): MACS‐sorted week 3 C9ORF72 mutant (iPSC91 and iPSC92) oligodendrocytes display comparable C9ORF72‐v2 and C9ORF72‐total (v1, v2, and v3 isoforms) expression compared with controls (iPS1 and iPS2) as showed by quantitative real‐time polymerase chain reaction (qRT‐PCR) (N = 5 for each line, unpaired t tests). (C): Fluorescence in situ hybridization showing the presence of nuclear GGGGCC RNA‐containing foci in both iPSC91 (N = 3) and iPSC92 (N = 3) O4+‐oligodendrocytes. Scale bar = 10 μm. (D): Percentage O4+‐oligodendrocytes derived from the iPSC91 and iPSC92 lines that express nuclear GGGGCC RNA‐containing foci at week 1 (iPSC91/iPSC92: N = 3/3) and 3 (iPSC91/iPSC92: N = 3/3). (E): Flow cytometry quantification of O4+ and caspase3‐7+ cells showing no differences in cell death across the mutant (iPSC91 and iPSC92) and control (iPS1 and iPS2) lines in basal conditions (N = 3 for each line, unpaired t tests). (F): MACS‐sorted week 3 C9ORF72 mutant (iPSC91 and iPSC92) oligodendrocytes display no differences in MCT1 expression compared with controls (iPS1 and iPS2) as showed by qRT‐PCR (N = 5 for each line, unpaired t tests). (G): Mean percentage reduction in rectification indices of currents recorded from week 3 O4+‐oligodendrocytes with respect to oligodendrocyte precursor cells (OPCs) (unpaired t tests). (H): Mean AMPAR conductance for PDGFRα+‐OPCs (iPSC91/iPSC92: n = 12/11, N = 3/3) and O4+‐oligodendrocytes (iPSC91/iPSC92: n = 4/5, N = 2/1) derived from the iPSC9 lines. *, p < 0.05; ***, p < 0.001, respectively. Abbreviations: DAPI, 4',6‐diamidino‐2‐phenylindole; iPS, induced pluripotent stem cell; MBP, myelin basic protein; PDGFRα, platelet‐derived growth factor receptor alpha.
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| Citation | PMID | DOI | Status |
|---|---|---|---|
| Al‐Sarraj S , King A , Troakes C et al. p62 positive, TDP‐43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72‐linked FTLD and MND/ALS. Acta Neuropathol 2011;122:691–702. 2210132310.1007/s00401-011-0911-2 | — | — | — |
| Barres BA , Koroshetz WJ , Swartz KJ et al. Ion channel expression by white matter glia: The O‐2A glial progenitor cell. Neuron 1990;4:507–524. 169100510.1016/0896-6273(90)90109-s | — | — | — |
| Belzil VV , Bauer PO , Prudencio M et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 2013;126:895–905. 2416661510.1007/s00401-013-1199-1PMC3830740 | — | — | — |
| Bilican B , Livesey MR , Haghi G et al. Physiological normoxia and absence of EGF is required for the long‐term propagation of anterior neural precursors from human pluripotent cells. Plos One 2014;9:e85932. 2446579610.1371/journal.pone.0085932PMC3895023 | — | — | — |
| Bilican B , Serio A , Barmada SJ et al. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP‐43 proteinopathies and reveal cell‐specific vulnerability. Proc Natl Acad Sci USA 2012;109:5803–5808. 2245190910.1073/pnas.1202922109PMC3326463 | — | — | — |
| Bradl M , Lassmann H . Oligodendrocytes: Biology and pathology. Acta Neuropathol 2010;119:37–53. 1984744710.1007/s00401-009-0601-5PMC2799635 | — | — | — |
| Brettschneider J , Arai K , Del Tredici K et al. TDP‐43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol 2014;128:423–437. 2491626910.1007/s00401-014-1299-6PMC4384652 | — | — | — |
| Brettschneider J , Van Deerlin VM , Robinson JL et al. Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol 2012;123:825–839. 2242685410.1007/s00401-012-0970-zPMC3521561 | — | — | — |
| Butts BD , Houde C , Mehmet H . Maturation‐dependent sensitivity of oligodendrocyte lineage cells to apoptosis: Implications for normal development and disease. Cell Death Differ 2008;15:1178–1186. 1848349010.1038/cdd.2008.70 | — | — | — |
| Chambers SM , Fasano CA , Papapetrou EP et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 2009;27:275–280. 1925248410.1038/nbt.1529PMC2756723 | — | — | — |
| Chittajallu R , Aguirre A , Gallo V . NG2‐positive cells in the mouse white and grey matter display distinct physiological properties. J Physiol 2004;561:109–122. 1535881110.1113/jphysiol.2004.074252PMC1665337 | — | — | — |
| Clarke LE , Young KM , Hamilton NB et al. Properties and fate of oligodendrocyte progenitor cells in the corpus callosum, motor cortex, and piriform cortex of the mouse. J Neurosci 2012;32:8173–8185. 2269989810.1523/JNEUROSCI.0928-12.2012PMC3378033 | — | — | — |
| Crawford AH , Stockley JH , Tripathi RB et al. Oligodendrocyte progenitors: Adult stem cells of the central nervous system? Exp Neurol 2014;260:50–55. 2480091310.1016/j.expneurol.2014.04.027 | — | — | — |
| De Biase LM , Nishiyama A , Bergles DE . Excitability and synaptic communication within the oligodendrocyte lineage. J Neurosci 2010;30:3600–3611. 2021999410.1523/JNEUROSCI.6000-09.2010PMC2838193 | — | — | — |
| DeJesus‐Hernandez M , Mackenzie IR , Boeve BF et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p‐linked FTD and ALS. Neuron 2011;72:245–256. 2194477810.1016/j.neuron.2011.09.011PMC3202986 | — | — | — |
| Dermitzakis ET , Clark AG . Evolution of transcription factor binding sites in Mammalian gene regulatory regions: Conservation and turnover. Mol Biol Evol 2002;19:1114–1121. 1208213010.1093/oxfordjournals.molbev.a004169 | — | — | — |
| Devlin AC , Burr K , Borooah S et al. Human iPSC‐derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat Commun 2015;6:5999. 2558074610.1038/ncomms6999PMC4338554 | — | — | — |
| Donnelly CJ , Zhang PW , Pham JT et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 2013;80:415–428. 2413904210.1016/j.neuron.2013.10.015PMC4098943 | — | — | — |
| Douvaras P , Wang J , Zimmer M et al. Efficient generation of myelinating oligodendrocytes from primary progressive multiple sclerosis patients by induced pluripotent stem cells. Stem Cell Reports 2014;3:250–259. 2525433910.1016/j.stemcr.2014.06.012PMC4176529 | — | — | — |
| Fannon J , Tarmier W , Fulton D . Neuronal activity and AMPA‐type glutamate receptor activation regulates the morphological development of oligodendrocyte precursor cells. Glia 2015. 10.1002/glia.2279925739948 | — | — | — |
| Follett PL , Deng W , Dai W et al. Glutamate receptor‐mediated oligodendrocyte toxicity in periventricular leukomalacia: A protective role for topiramate. J Neurosci 2004;24:4412–4420. 1512885510.1523/JNEUROSCI.0477-04.2004PMC6729451 | — | — | — |
| Fratta P , Mizielinska S , Nicoll AJ et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G‐quadruplexes. Sci Rep 2012;2:1016. 2326487810.1038/srep01016PMC3527825 | — | — | — |
| Fratta P , Poulter M , Lashley T et al. Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol 2013;126:401–409. 2381806510.1007/s00401-013-1147-0PMC3753468 | — | — | — |
| Freibaum BD , Lu Y , Lopez‐Gonzalez R et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 2015;525:129–133. 2630889910.1038/nature14974PMC4631399 | — | — | — |
| Gijselinck I , Van Langenhove T , van der Zee J et al. A C9orf72 promoter repeat expansion in a Flanders‐Belgian cohort with disorders of the frontotemporal lobar degeneration‐amyotrophic lateral sclerosis spectrum: A gene identification study. Lancet Neurol 2012;11:54–65. 2215478510.1016/S1474-4422(11)70261-7 | — | — | — |
| Hu BY , Du ZW , Zhang SC . Differentiation of human oligodendrocytes from pluripotent stem cells. Nat Protoc 2009;4:1614–1622. 1983447610.1038/nprot.2009.186PMC2789118 | — | — | — |
| Husseini L , Schmandt T , Scheffler B et al. Functional analysis of embryonic stem cell‐derived glial cells after integration into hippocampal slice cultures. Stem Cells Dev 2008;17:1141–1152. 1900645410.1089/scd.2007.0244 | — | — | — |
| Itoh T , Beesley J , Itoh A et al. AMPA glutamate receptor‐mediated calcium signaling is transiently enhanced during development of oligodendrocytes. J Neurochem 2002;81:390–402. 1206448610.1046/j.1471-4159.2002.00866.x | — | — | — |
| Janke C , Beck M , Stahl T et al. Phylogenetic diversity of the expression of the microtubule‐associated protein tau: Implications for neurodegenerative disorders. Brain Res Mol Brain Res 1999;68:119–128. 1032078910.1016/s0169-328x(99)00079-0 | — | — | — |
| Jiang P , Chen C , Liu XB et al. Generation and characterization of spiking and nonspiking oligodendroglial progenitor cells from embryonic stem cells. Stem Cells 2013;31:2620–2631. 2394000310.1002/stem.1515PMC3923867 | — | — | — |
| Kang SH , Li Y , Fukaya M et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 2013;16:571–579. 2354268910.1038/nn.3357PMC3637847 | — | — | — |
| Karadottir R , Attwell D . Neurotransmitter receptors in the life and death of oligodendrocytes. Neuroscience 2007;145:1426–1438. 1704917310.1016/j.neuroscience.2006.08.070PMC2173944 | — | — | — |
| Karadottir R , Hamilton NB , Bakiri Y et al. Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nat Neurosci 2008;11:450–456. 1831113610.1038/nn2060PMC2615224 | — | — | — |
| Koike M , Iino M , Ozawa S . Blocking effect of 1‐naphthyl acetyl spermine on Ca(2+)‐permeable AMPA receptors in cultured rat hippocampal neurons. Neurosci Res 1997;29:27–36. 929349010.1016/s0168-0102(97)00067-9 | — | — | — |
| Koppers M , Blokhuis AM , Westeneng HJ et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann Neurol 2015;78:426–438. 2604455710.1002/ana.24453PMC4744979 | — | — | — |
| Kukley M , Nishiyama A , Dietrich D . The fate of synaptic input to NG2 glial cells: Neurons specifically downregulate transmitter release onto differentiating oligodendroglial cells. J Neurosci 2010;30:8320–8331. 2055488310.1523/JNEUROSCI.0854-10.2010PMC6634580 | — | — | — |
| Lee Y , Morrison BM , Li Y et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 2012;487:443–448. 2280149810.1038/nature11314PMC3408792 | — | — | — |
| Livesey MR , Bilican B , Qiu J et al. Maturation of AMPAR composition and the GABAAR reversal potential in hPSC‐derived cortical neurons. J Neurosci 2014;34:4070–4075. 2462378410.1523/JNEUROSCI.5410-13.2014PMC3951701 | — | — | — |
| Majounie E , Renton AE , Mok K et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross‐sectional study. Lancet Neurol 2012;11:323–330. 2240622810.1016/S1474-4422(12)70043-1PMC3322422 | — | — | — |
| Maldonado PP , Velez‐Fort M , Levavasseur F et al. Oligodendrocyte precursor cells are accurate sensors of local K + in mature gray matter. J Neurosci 2013;33:2432–2442. 2339267210.1523/JNEUROSCI.1961-12.2013PMC6619152 | — | — | — |
| Meucci O , Fatatis A , Holzwarth JA et al. Developmental regulation of the toxin sensitivity of Ca2+‐permeable AMPA receptors in cortical glia. J Neurosci 1996;16:519–530. 855133610.1523/JNEUROSCI.16-02-00519.1996PMC2690449 | — | — | — |
| Meyer K , Ferraiuolo L , Miranda CJ et al. Direct conversion of patient fibroblasts demonstrates non‐cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A 2014;111:829–832. 2437937510.1073/pnas.1314085111PMC3896192 | — | — | — |
| Mizielinska S , Lashley T , Norona FE et al. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol 2013;126:845–857. 2417009610.1007/s00401-013-1200-zPMC3830745 | — | — | — |
| Murray ME , DeJesus‐Hernandez M , Rutherford NJ et al. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 2011;122:673–690. 2208325410.1007/s00401-011-0907-yPMC3277860 | — | — | — |
| Neusch C , Rozengurt N , Jacobs RE et al. Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci 2001;21:5429–5438. 1146641410.1523/JNEUROSCI.21-15-05429.2001PMC6762664 | — | — | — |
| Oberheim NA , Takano T , Han X et al. Uniquely hominid features of adult human astrocytes. J Neurosci 2009;29:3276–3287. 1927926510.1523/JNEUROSCI.4707-08.2009PMC2819812 | — | — | — |
| Odom DT , Dowell RD , Jacobsen ES et al. Tissue‐specific transcriptional regulation has diverged significantly between human and mouse. Nat Genet 2007;39:730–732. 1752997710.1038/ng2047PMC3797512 | — | — | — |
| Patneau DK , Wright PW , Winters C et al. Glial cells of the oligodendrocyte lineage express both kainate‐ and AMPA‐preferring subtypes of glutamate receptor. Neuron 1994;12:357–371. 750916010.1016/0896-6273(94)90277-1 | — | — | — |
| Philips T , Bento‐Abreu A , Nonneman A et al. Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain 2013;136:471–482. 2337821910.1093/brain/aws339PMC3572934 | — | — | — |
| Reddy K , Zamiri B , Stanley SY et al. The disease‐associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length‐dependent uni‐ and multimolecular RNA G‐quadruplex structures. J Biol Chem 2013;288:9860–9866. 2342338010.1074/jbc.C113.452532PMC3617286 | — | — | — |
| Renton AE , Majounie E , Waite A et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21‐linked ALS‐FTD. Neuron 2011;72:257–268. 2194477910.1016/j.neuron.2011.09.010PMC3200438 | — | — | — |
| Saab AS , Tzvetanova ID , Nave KA . The role of myelin and oligodendrocytes in axonal energy metabolism. Curr Opin Neurobiol 2013;23:1065–1072. 2409463310.1016/j.conb.2013.09.008 | — | — | — |
| Sareen D , O'Rourke JG , Meera P et al. Targeting RNA foci in iPSC‐derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 2013;5:208ra149. 10.1126/scitranslmed.3007529PMC409094524154603 | — | — | — |
| Scheffler B , Schmandt T , Schroder W et al. Functional network integration of embryonic stem cell‐derived astrocytes in hippocampal slice cultures. Development 2003;130:5533–5541. 1453029810.1242/dev.00714 | — | — | — |
| Sim FJ , McClain CR , Schanz SJ et al. CD140a identifies a population of highly myelinogenic, migration‐competent and efficiently engrafting human oligodendrocyte progenitor cells. Nat Biotechnol 2011;29:934–941. 2194702910.1038/nbt.1972PMC3365580 | — | — | — |
| Smith BN , Newhouse S , Shatunov A et al. The C9ORF72 expansion mutation is a common cause of ALS+/‐FTD in Europe and has a single founder. Eur J Hum Genet 2013;21:102–108. 2269206410.1038/ejhg.2012.98PMC3522204 | — | — | — |
| Sontheimer H , Trotter J , Schachner M et al. Channel expression correlates with differentiation stage during the development of oligodendrocytes from their precursor cells in culture. Neuron 1989;2:1135–1145. 256038610.1016/0896-6273(89)90180-3 | — | — | — |
| Stacpoole SR , Spitzer S , Bilican B et al. High yields of oligodendrocyte lineage cells from human embryonic stem cells at physiological oxygen tensions for evaluation of translational biology. Stem Cell Reports 2013;1:437–450. 2428603110.1016/j.stemcr.2013.09.006PMC3841262 | — | — | — |
| Suzuki N , Maroof AM , Merkle FT et al. The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD. Nat Neurosci 2013;16:1725–1727. 2418542510.1038/nn.3566PMC4397902 | — | — | — |
| Swanson GT , Kamboj SK , Cull‐Candy SG . Single‐channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. J Neurosci 1997;17:58–69. 898773610.1523/JNEUROSCI.17-01-00058.1997PMC6793687 | — | — | — |
| Traynelis SF , Wollmuth LP , McBain CJ et al. Glutamate receptor ion channels: Structure, regulation, and function. Pharmacol Rev 2010;62:405–496. 2071666910.1124/pr.109.002451PMC2964903 | — | — | — |
| Tripathi RB , Clarke LE , Burzomato V et al. Dorsally and ventrally derived oligodendrocytes have similar electrical properties but myelinate preferred tracts. J Neurosci 2011;31:6809–6819. 2154361110.1523/JNEUROSCI.6474-10.2011PMC4227601 | — | — | — |
| Van den Eynden J , Ali SS , Horwood N et al. Glycine and glycine receptor signalling in non‐neuronal cells. Front Mol Neurosci 2009;2:9. 1973891710.3389/neuro.02.009.2009PMC2737430 | — | — | — |
| Wang S , Bates J , Li X et al. Human iPSC‐derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 2013;12:252–264. 2339544710.1016/j.stem.2012.12.002PMC3700553 | — | — | — |
| Wilson MD , Barbosa‐Morais NL , Schmidt D et al. Species‐specific transcription in mice carrying human chromosome 21. Science 2008;322:434–438. 1878713410.1126/science.1160930PMC3717767 | — | — | — |
| Wosik K , Ruffini F , Almazan G et al. Resistance of human adult oligodendrocytes to AMPA/kainate receptor‐mediated glutamate injury. Brain 2004;127:2636–2648. 1550962410.1093/brain/awh302 | — | — | — |
| Zamiri B , Reddy K , Macgregor RB, Jr. et al. TMPyP4 porphyrin distorts RNA G‐quadruplex structures of the disease‐associated r(GGGGCC)n repeat of the C9orf72 gene and blocks interaction of RNA‐binding proteins. J Biol Chem 2014;289:4653–4659. 2437114310.1074/jbc.C113.502336PMC3931028 | — | — | — |
| Zhang K , Donnelly CJ , Haeusler AR et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 2015;525:56–61. 2630889110.1038/nature14973PMC4800742 | — | — | — |
| Zonouzi M , Renzi M , Farrant M et al. Bidirectional plasticity of calcium‐permeable AMPA receptors in oligodendrocyte lineage cells. Nat Neurosci 2011;14:1430–1438. 2198368310.1038/nn.2942PMC3204222 | — | — | — |
In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells? | 2018 | 29897633 |
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Are oligodendrocytes bystanders or drivers of Parkinson's disease pathology? | Salazar Campos JM et al. | — | 2025 | → |
| Magnetically reshapable 3D multi-electrode arrays of liquid metals for electrophysiological analysis of brain organoids. | Kim E et al. | — | 2025 | → |
| Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function. | Kazakou NL et al. | — | 2025 | → |
| Protocol for assessing myelination by human iPSC-derived oligodendrocytes in Shiverer mouse ex vivo brain slice cultures. | Tsarouchas TM et al. | — | 2025 | → |
| Revisiting oligodendrocytes in amyotrophic lateral sclerosis using human multicellular stem cell models. | Mouhi S et al. | — | 2025 | → |
| Role of Oligodendrocyte Lineage Cells in White Matter Injury. | Pieczonka K et al. | — | 2025 | → |
| Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology. | Wang J et al. | — | 2025 | → |
| The Fragile X Messenger Ribonucleoprotein 1 Regulates the Morphology and Maturation of Human and Rat Oligodendrocytes. | Ramesh V et al. | — | 2025 | → |
| Towards an integrated approach for understanding glia in Amyotrophic Lateral Sclerosis. | Majewski S et al. | — | 2025 | → |
| CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents. | Wagstaff LJ et al. | — | 2024 | → |
| Graft-derived neurons and bystander effects are maintained for six months after human iPSC-derived NESC transplantation in mice's cerebella. | Mendonça LS et al. | — | 2024 | → |
| Oligodendrocytes in Huntington's Disease: A Review of Oligodendrocyte Pathology and Current Cell Reprogramming Approaches for Oligodendrocyte Modelling of Huntington's Disease. | Back AM et al. | — | 2024 | → |
| Cell reprogramming for oligodendrocytes: A review of protocols and their applications to disease modeling and cell-based remyelination therapies. | McCaughey-Chapman A et al. | — | 2023 | → |
| Developing a human iPSC-derived three-dimensional myelin spheroid platform for modeling myelin diseases. | Feng L et al. | — | 2023 | → |
| Extracellular vesicle-associated cholesterol supports the regenerative functions of macrophages in the brain. | Vanherle S et al. | — | 2023 | → |
| Technical approaches and challenges to study AMPA receptors in oligodendrocyte lineage cells: Past, present, and future. | Perez-Gianmarco L et al. | — | 2023 | → |
| Therapeutical growth in oligodendroglial fate induction via transdifferentiation of stem cells for neuroregenerative therapy. | Dwivedi S et al. | — | 2023 | → |
| Utilizing hiPSC-derived oligodendrocytes to study myelin pathophysiology in neuropsychiatric and neurodegenerative disorders. | Shim G et al. | — | 2023 | → |
| What Are the Roles of Oligodendrocyte Precursor Cells in Normal and Pathologic Conditions? | Benarroch E | — | 2023 | → |
| Disease Modeling of Neurodegenerative Disorders Using Direct Neural Reprogramming. | Legault EM et al. | — | 2022 | → |
| Generation of neuronal/glial mixed cultures from human induced pluripotent stem cells (hiPSCs). | Mangiameli E et al. | — | 2022 | → |
| Human iPSC-Derived Neural Models for Studying Alzheimer's Disease: from Neural Stem Cells to Cerebral Organoids. | Barak M et al. | — | 2022 | → |
| The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic hedgehog signaling. | Schembs L et al. | — | 2022 | → |
| Using MS induced pluripotent stem cells to investigate MS aetiology. | Fortune AJ et al. | — | 2022 | → |
| 3D hydrogel models of the neurovascular unit to investigate blood-brain barrier dysfunction. | Potjewyd G et al. | — | 2021 | → |
| Age-related loss of axonal regeneration is reflected by the level of local translation. | van Erp S et al. | — | 2021 | → |
| Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases. | Valori CF et al. | — | 2021 | → |
| Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis. | Traiffort E et al. | — | 2021 | → |
| Dysfunction of oligodendrocyte inwardly rectifying potassium channel in a rat model of amyotrophic lateral sclerosis. | Peric M et al. | — | 2021 | → |
| iPSC-derived myelinoids to study myelin biology of humans. | James OG et al. | — | 2021 | → |
| Metabolic and immune dysfunction of glia in neurodegenerative disorders: Focus on iPSC models. | Rõlova T et al. | — | 2021 | → |
| Proteostatic imbalance and protein spreading in amyotrophic lateral sclerosis. | Cicardi ME et al. | — | 2021 | → |
| Remyelination: what are the prospects for regenerative therapies in multiple sclerosis? | Moore JD | — | 2021 | → |
| Single Transcription Factor-Based Differentiation Allowing Fast and Efficient Oligodendrocyte Generation via SOX10 Overexpression. | Neyrinck K et al. | — | 2021 | → |
| The ciliary gene <i>INPP5E</i> confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic Hedgehog signalling | Schembs L et al. | — | 2021 | — |
| Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model. | Barton SK et al. | — | 2021 | → |
| Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia. | Albert K et al. | — | 2021 | → |
| Changes of white matter microstructure after successful treatment of bipolar depression. | Melloni EMT et al. | — | 2020 | → |
| Continuous Immune-Modulatory Effects of Human Olig2+ Precursor Cells Attenuating a Chronic-Active Model of Multiple Sclerosis. | Nishri Y et al. | — | 2020 | → |
| Mechanical regulation of oligodendrocyte biology. | Makhija EP et al. | — | 2020 | → |
| Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo. | Mozafari S et al. | — | 2020 | → |
| Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. | Marton RM et al. | — | 2019 | → |
| Electrophysiological Properties of Adult Zebrafish Oligodendrocyte Progenitor Cells. | Tsata V et al. | — | 2019 | → |
| Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction. | Vasistha NA et al. | — | 2019 | → |
| Glutamatergic signaling between neurons and oligodendrocyte lineage cells: Is it synaptic or non-synaptic? | Kula B et al. | — | 2019 | → |
| In Vitro Generation and Electrophysiological Characterization of OPCs and Oligodendrocytes from Human Pluripotent Stem Cells. | Magnani D et al. | — | 2019 | → |
| A Homer 1 gene variant influences brain structure and function, lithium effects on white matter, and antidepressant response in bipolar disorder: A multimodal genetic imaging study. | Benedetti F et al. | — | 2018 | → |
| C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca<sup>2+</sup>-permeable AMPA receptor-mediated excitotoxicity. | Selvaraj BT et al. | — | 2018 | → |
| Generation of defined neural populations from pluripotent stem cells. | McComish SF et al. | — | 2018 | → |
| Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells? | Prytkova I et al. | — | 2018 | → |
| Modelling Sporadic Alzheimer's Disease Using Induced Pluripotent Stem Cells. | Rowland HA et al. | — | 2018 | → |
| Representing Diversity in the Dish: Using Patient-Derived <i>in Vitro</i> Models to Recreate the Heterogeneity of Neurological Disease. | Ghaffari LT et al. | — | 2018 | → |
| Stem cells and cell-based therapies for cerebral palsy: a call for rigor. | Jantzie LL et al. | — | 2018 | → |
| Defined and Scalable Differentiation of Human Oligodendrocyte Precursors from Pluripotent Stem Cells in a 3D Culture System. | Rodrigues GMC et al. | — | 2017 | → |
| Drug discovery for remyelination and treatment of MS. | Cole KLH et al. | — | 2017 | → |
| Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis. | Rajda C et al. | — | 2017 | → |
| In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers. | DeJesus-Hernandez M et al. | — | 2017 | → |
| Modeling Human Neurological and Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Neuronal Differentiation and Its Applications in Neurotrauma. | Bahmad H et al. | — | 2017 | → |
| Modeling the C9ORF72 repeat expansion mutation using human induced pluripotent stem cells. | Selvaraj BT et al. | — | 2017 | → |
| Prospects for Modeling Abnormal Neuronal Function in Schizophrenia Using Human Induced Pluripotent Stem Cells. | Prytkova I et al. | — | 2017 | → |
| Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism. | Ferraiuolo L et al. | — | 2016 | → |
| The Stagnant Adaptation of Defined and Xeno-Free Culture of iPSCs in Academia. | Vecchi JT et al. | — | 2015 | → |