The influence of retinoic acid on the human oligodendrocyte precursor cells by RNA-sequencing

Kim, Sun Young; Kelland, Eve E.; Kim, Ji hong; Lund, Brett T.; Chang, Xiao; Wang, Kai; Weiner, Leslie P.

doi:10.1016/j.bbrep.2016.12.004

Cited by 5 publications

(7 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RARα has been shown to be constitutively present in OPCs and to be transiently increased by RA (Laeng et al, 1994), probably RARα2, because only this isoform has been reported to be induced by RA (Leroy et al, 1991), whereas RARβ is not constitutively expressed in OPCs (Laeng et al, 1994). However, prolonged treatment of human-derived OPCs with RA results in RARβ upregulation and in the upregulation of two known transcriptional inhibitors of oligodendrocyte differentiation, Hes5 and Id4 (Kim et al, 2017). In embryonic SC, where relatively high levels of retinoids are present, RA was found to inhibit oligodendrocyte differentiation during early embryonic development, permitting OPCs dispersal throughout the entire SC (Noll and Miller, 1994).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

Goncalves

Clarke

et al. 2019

J. Neurosci.

View full text Add to dashboard Cite

In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARβ) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARβ agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2 + cells) in a decorin-mediated neuron–glia cross talk. Decorin promoted the activation of RARα in NG2 + cells by increasing the availability of the endogenous ligand RA. NG2 + cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR–calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARβ and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination. SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARβ) and RARα in NG2 + cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARβ agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin–Ca 2+ pathway. Although RARβ has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARβ and RARα in remyelination.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

Goncalves

Clarke

et al. 2019

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The 2 most highly differentially expressed proteins (mhDEPs, with log 2 fold-change ≥ 5) on d20, MDK and RBP1, truly reflect the role of this leading step, the pre-OPC stage, in OL generation. Both mhDEPs instigate pre-OPC specification toward OL differentiation [ 114–117 ]. Among the 22 DEPs at the pre-OPC stage (Fig.…”

Section: Data Descriptionmentioning

confidence: 99%

“…S5 ). The correlation of this differential repatterning with the high abundance of known pre-OPC proteins such as MDK, RBP1 [ 114–117 ], SOX3 [ 118 ], and TNFRSF10B [ 119 ] points to the potential of these d20 DEPS to be used as biomarkers for the pre-OPC state.…”

Section: Data Descriptionmentioning

confidence: 99%

“…7F ). At this point, downregulation of NPC (d12) related STSPs such as FREM2 [ 108 ], DSP [ 150 ], TPP1 [ 100 ], KRT7 [ 151 ], KRT8 [ 152 , 153 ], and KRT18 [ 154 ] was accompanied by upregulation of epigenetic factors and transcription regulators (e.g., MDK, HIST1H1C, HIST1H1E, H1FX, H2AFX, HMGA2, HIST1H3A, H1F0, SOX3, H2AFZ, HIST1H1B, H2AFY, HIST2H2AB, TAGLN3, and HIST1H2BM [ 107 ]) and some well-known pre-OPC STSPs (e.g., MDK, RBP1 [ 114–117 ], DCHS1 [ 155 ], SOX3 [ 118 ], MAP1B [ 156 ], DPYSL4, DPYSL5 [ 157 , 158 ], TF [ 159 ], and TNFRSF10B [ 119 ]) (Fig. 7F ).…”

Section: Data Descriptionmentioning

confidence: 99%

See 1 more Smart Citation

The Dynamic Proteome of Oligodendrocyte Lineage Differentiation Features Planar Cell Polarity and Macroautophagy Pathways

et al. 2020

View full text Add to dashboard Cite

Background Generation of oligodendrocytes is a sophisticated multistep process, the mechanistic underpinnings of which are not fully understood and demand further investigation. To systematically profile proteome dynamics during human embryonic stem cell differentiation into oligodendrocytes, we applied in-depth quantitative proteomics at different developmental stages and monitored changes in protein abundance using a multiplexed tandem mass tag-based proteomics approach. Findings Our proteome data provided a comprehensive protein expression profile that highlighted specific expression clusters based on the protein abundances over the course of human oligodendrocyte lineage differentiation. We identified the eminence of the planar cell polarity signalling and autophagy (particularly macroautophagy) in the progression of oligodendrocyte lineage differentiation—the cooperation of which is assisted by 106 and 77 proteins, respectively, that showed significant expression changes in this differentiation process. Furthermore, differentially expressed protein analysis of the proteome profile of oligodendrocyte lineage cells revealed 378 proteins that were specifically upregulated only in 1 differentiation stage. In addition, comparative pairwise analysis of differentiation stages demonstrated that abundances of 352 proteins differentially changed between consecutive differentiation time points. Conclusions Our study provides a comprehensive systematic proteomics profile of oligodendrocyte lineage cells that can serve as a resource for identifying novel biomarkers from these cells and for indicating numerous proteins that may contribute to regulating the development of myelinating oligodendrocytes and other cells of oligodendrocyte lineage. We showed the importance of planar cell polarity signalling in oligodendrocyte lineage differentiation and revealed the autophagy-related proteins that participate in oligodendrocyte lineage differentiation.

show abstract

“…Oli-neuM express Myrf [8,19,52]; thus, we concentrated our attention on nuclear factors acting downstream of Myrf expression. Of these, the 9-cis retinoic acid-responsive element RXRγ is known to be upregulated at the transition from NPCs to the OPC lineage [53], as well as at lesions in the lysolecithin-induced murine demyelination model [54]. Furthermore, we have previously shown that the RXRγ inhibitor UV3003 downregulates MBP expression upon Clobetasol or Halcinonide treatment of Oli-neuM [8].…”

Section: Resultsmentioning

confidence: 99%

EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP

Nocita

Giovane

Tiberi

et al. 2019

Cells

View full text Add to dashboard Cite

Remyelination in the adult brain relies on the reactivation of the Neuronal Precursor Cell (NPC) niche and differentiation into Oligodendrocyte Precursor Cells (OPCs) as well as on OPC maturation into myelinating oligodendrocytes (OLs). These two distinct phases in OL development are defined by transcriptional and morphological changes. How this differentiation program is controlled remains unclear. We used two drugs that stimulate myelin basic protein (MBP) expression (Clobetasol and Gefitinib) alone or combined with epidermal growth factor receptor (EGFR) or Retinoid X Receptor gamma (RXRγ) gene silencing to decode the receptor signaling required for OPC differentiation in myelinating OLs. Electrospun polystyrene (PS) microfibers were used as synthetic axons to study drug efficacy on fiber engagement. We show that EGFR inhibition per se stimulates MBP expression and increases Clobetasol efficacy in OPC differentiation. Consistent with this, Clobetasol and Gefitinib co-treatment, by co-regulating RXRγ, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment.

show abstract

The influence of retinoic acid on the human oligodendrocyte precursor cells by RNA-sequencing

Cited by 5 publications

References 38 publications

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

The Dynamic Proteome of Oligodendrocyte Lineage Differentiation Features Planar Cell Polarity and Macroautophagy Pathways

EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP

Contact Info

Product

Resources

About