MiR-124 Enriched Exosomes Promoted the M2 Polarization of Microglia and Enhanced Hippocampus Neurogenesis After Traumatic Brain Injury by Inhibiting TLR4 Pathway

Yang, Yongxiang; Ye, Yuqin; Kong, Chuiguang; Su, Xinhong; Zhang, Xin; Bai, Wei; He, Xiaosheng

doi:10.1007/s11064-018-02714-z

Cited by 170 publications

(106 citation statements)

References 52 publications

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“…In one study delivering recombinant IL-4 after stroke in IL-4 knockout mice, repeated measures were not accounted for and wild-type mice were not tested (52). A variety of other approaches to TBI that promote an M2-like response have also observed improvement in behavioral outcomes (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) (31)(32)(33)(34)(35)(36). However, in many of these studies, behavior is not (or could not be) assessed prior to treatment to ensure the absence of accidental bias.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Enam

Kader

Bodkin

et al. 2020

Preprint

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Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity. There already exists clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as Interleukin-4 (IL-4). To enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs to transiently express IL-4 via synthetic IL-4 mRNA. We observed that these IL-4 expressing MSCs indeed induce a robust M2like macrophage phenotype and promote anti-inflammatory gene expression in a modified TBI model of closed head injury. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes. This suggests that an acute enrichment of M2like macrophages cannot solely orchestrate the neurogenesis, axonal regeneration, and improved WMI after diffuse TBI. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists in spite of acute enrichment of M2-like macrophages in the brain. Last, we comment on our modified TBI model, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.

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Section: Discussionmentioning

confidence: 99%

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Enam

Kader

Bodkin

et al. 2020

Preprint

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“…In previous studies, Mun found that the expression of miR-29b-3p was elevated in the cochlea of aged C57BL/6 mice [28], which was consistent with our analysis. For others, miR-29a-3p, miR-29c-3p and miR-124-3p were mainly related to cancer [29][30][31][32][33][34], AD [35,36], and miR-124-3p also related to neurogenesis [37,38] and depression [39], with no research related to hearing loss.…”

Section: Discussmentioning

confidence: 97%

Screening of key genes and miRNAs involved in age-related hearing loss

song¹,

Zhang²,

Sun³

et al. 2020

Preprint

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Background Age-related hearing loss (ARHL) is the most common sensory deficit and refers to the gradual loss of hearing function with age. We aimed to research the differential expression genes during the occur of ARHL and explore microRNAs that maybe regulate these genes. Methods Search the GEO data GSE6045, GSE35234, GSE62173, GSE45026 from NCBI's Gene Expression Omnibus database, and analyze in R. Normalize GEO data by RMA method in R, and use linear microarray data model (LIMMA) method in R to compare young and old mice to find differential genes and microRNAs. Results 109 up-regulated and 121 down-regulated important genes were identified respectively. Functional enrichment shows that they are significantly enriched in protein digestion and absorption, neuroactive ligand-receptor interaction, and PI3K-Akt signaling pathway. Among the top 20 Hub genes, 7 down-regulated genes (Col3a1, Col1a2, Sparc, Col4a2, Col2a1, Lox, Sparc, Ctgf) have verified targeted miRNAs, which have interaction with differential miRNAs of GSE45026. Finally, we designated miR-29a-3p, miR-29b-3p, miR-29c-3p, and miR-124-3p as key miRNAs involved in the development of age-related hearing loss. Conclusions These low expression genes of Col3a1, Col1a2, Sparc, Col4a2, Col2a1,Lox, Sparc, and Ctgf maybe key genes of ARHL, and probably regulated by miR-29a-3p, miR-29b-3p, miR-29c-3p, and miR-124-3p.

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“…Thus, it is tempting to design a preclinical trial of EV injection into an ischemic stroke animal model to induce anti‐inflammatory effects through interactions with microglia . A study of miR‐124‐enriched EV administration is planned, and miR‐124 has been proven to shift microglia to the M2 phenotype to benefit neurogenesis . In addition, in virtue of this potent carrier, there will be more promising clinical studies of EVs transplantation to shape microglia after stroke in the near future.…”

Section: Microglia‐neighboring Cells Crosstalk and Interventions For mentioning

confidence: 99%

“…82 A study of miR-124-enriched EV administration is planned, and miR-124 has been proven to shift microglia to the M2 phenotype to benefit neurogenesis. 83 In addition, in virtue of this potent carrier, there will be more promising clinical studies of EVs transplantation to shape microglia after stroke in the near future. Ubiquitin-specific protease 18 has been reported to reduce the levels of proinflammatory cytokines and JAK/STAT pathway members in oxygen/glucose-deprived BV2 microglia and promote neurogenesis in MCAO mice.…”

Section: Neuron-microglia Crosstalk In Strokementioning

confidence: 99%

Potential microglia‐based interventions for stroke

Huang

Yang

et al. 2020

CNS Neurosci Ther

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A large number of families worldwide suffer from the physical and mental burden posed by stroke. An increasing number of studies aimed at the prevention and treatment of stroke have been conducted. Specifically, manipulating the immune response to stroke is under intense investigation. Microglia are the principal immune cells in the brain and are the first line of defense against the pathophysiology induced by stroke. Increasing evidence has suggested that microglia play diverse roles that depend on dynamic interactions with neurons, astrocytes, and other neighboring cells both in the normal brain and under pathological conditions, including stroke. Moreover, there are dynamic alterations in microglial functions with respect to aging and sex differences in the human brain, which offer a deep understanding of the conditions of stroke patients of different ages and sex. Hence, we review the dynamic microglial reactions caused by aging, sex, and crosstalk with neighboring cells both in normal conditions and after stroke and relevant potential interventions.

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MiR-124 Enriched Exosomes Promoted the M2 Polarization of Microglia and Enhanced Hippocampus Neurogenesis After Traumatic Brain Injury by Inhibiting TLR4 Pathway

Cited by 170 publications

References 52 publications

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Screening of key genes and miRNAs involved in age-related hearing loss

Potential microglia‐based interventions for stroke

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