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Published on: November 23, 2014
Long non-coding RNA Malat1 modulates CXCR4 expression to regulate the interaction between induced neural stem cells
Qin Dong1, Pengyu Chen2, Wenqiao Qiu3
1Department of Neurology, Fu Xing Hospital, Capital Medical University, Beijing, 100038, China.
Background:
Closed head injury (CHI) provokes a prominent neuroinflammation that may lead to long-term health consequences. Microglia plays pivotal and complex roles in neuroinflammation-mediated neuronal insult and repair following CHI. We previously reported that induced neural stem cells (iNSCs) can block the effects of CXCL12/CXCR4 signaling on NF-κB activation in activated microglia by CXCR4 overexpression. Here we aim to uncover the mechanism of CXCR4 upregulation in iNSCs.
Methods:
We performed bioinformatic analysis to detect the differentially expressed genes in iNSCs after co-cultured with LPS-activated microglia. Subsequently, we predicted the target genes and performed gain- and loss-of-functional studies, dualluciferase reporter, RNA immunoprecipitation, biotin-coupled miRNA pulldown, fluorescence in situ hybridization and cell transplantation assays to further elucidate the mechanism underlying the immunoregulatory effects of iNSCs. Student's t-test and one-way analysis of variance (ANOVA) with Tukey's post hoc test were used to determine statistical significance.
Results:
Our results indicated that Malat1 could act as a sponge of miR-139-5p to modulate the expression of CXCR4 that exerted significant influence on the immunoregulatory effects of iNSCs on the secretion of CXCL12, TNF-α and IGF-1 by activated microglia. Furthermore, Malat1 inhibition blocked the immunoregulatory effects of iNSC grafts on microglial activation as well as neuroinflammation in the injured cortices of CHI mice. Interestingly, NF-κB activation in iNSCs augmented the immunoregulatory effects of iNSCs on microglial activation by activating the axis of Malat1/miR-139-5p/Cxcr4. Notably, we found that TNF-α secreted by activated microglia could bind to TNFR1 at the surface of iNSCs to trigger NF-κB activation in iNSCs.
Conclusions:
In short, our findings reveal a novel role of Malat1 in the immunomodulatory effects of iNSCs on microglial activation, suggesting that transplanted iNSCs may self-perceive the changes of the activated state of microglia and thus make prudential regulation of the neuroinflammation following CHI.
Insights
Induced neural stem cells (iNSCs) regulate neuroinflammation after closed head injury (CHI) by modulating microglial activation via the Malat1/miR-139-5p/CXCR4 axis. This pathway enhances iNSC immunomodulatory effects, offering therapeutic potential for CHI.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- Closed head injury (CHI) triggers significant neuroinflammation, impacting long-term brain health.
- Microglia play a crucial role in neuroinflammation, neuronal damage, and repair post-CHI.
- Induced neural stem cells (iNSCs) have shown potential in mitigating CHI's effects by modulating microglial activation.
Purpose of the Study:
- To elucidate the mechanism by which iNSCs upregulate CXCR4 expression.
- To investigate the role of Malat1, miR-139-5p, and CXCR4 in iNSC-mediated immunomodulation following CHI.
- To understand how iNSCs sense and respond to microglial activation states.
Main Methods:
- Bioinformatic analysis of differentially expressed genes in iNSCs co-cultured with activated microglia.
- Gain- and loss-of-functional studies, dual-luciferase reporter assays, RNA immunoprecipitation, and miRNA pulldown assays.
- In vivo cell transplantation assays in CHI mouse models and statistical analysis (t-test, ANOVA).
Main Results:
- Malat1 acts as a sponge for miR-139-5p, regulating CXCR4 expression and influencing iNSC immunomodulatory effects on microglia.
- Inhibition of Malat1 impaired the therapeutic effects of iNSC grafts on microglial activation and neuroinflammation in CHI mice.
- NF-κB activation in iNSCs, triggered by microglial TNF-α, enhances the Malat1/miR-139-5p/CXCR4 axis, boosting immunomodulatory capacity.
Conclusions:
- Malat1 plays a critical role in the immunomodulatory functions of iNSCs on microglial activation.
- Transplanted iNSCs can sense microglial activation states and prudently regulate neuroinflammation post-CHI.
- The Malat1/miR-139-5p/CXCR4 axis represents a novel mechanism for iNSC-mediated neuroprotection in CHI.
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