Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent ...molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer’s disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
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•Microglia associated with neuritic Aβ-plaques exhibit a neurodegenerative phenotype•Phagocytosis of apoptotic neurons suppresses homeostatic microglia•The TREM2-APOE pathway regulates neurodegenerative microglial phenotypic switch•Targeting APOE signaling restores homeostatic and tolerogenic microglia
Microglia change their phenotype and function during aging and neurodegeneration, but the underlying molecular mechanisms for this change remain unknown. Krasemann et al. identify the TREM2-APOE pathway as a major regulator of microglia phenotypic change in neurodegenerative diseases and suggest that targeting this pathway could restore homeostatic microglia.
Although regenerative medicine is searching for pluripotent stem cells that could be employed for therapy, various types of more differentiated adult stem and progenitor cells are in meantime being ...employed in clinical trials to regenerate damaged organs (for example, heart, kidney or neural tissues). It is striking that, for a variety of these cells, the currently observed final outcomes of cellular therapies are often similar. This fact and the lack of convincing documentation for donor-recipient chimerism in treated tissues in most of the studies indicates that a mechanism other than transdifferentiation of cells infused systemically into peripheral blood or injected directly into damaged organs may have an important role. In this review, we will discuss the role of (i) growth factors, cytokines, chemokines and bioactive lipids and (ii) microvesicles (MVs) released from cells employed as cellular therapeutics in regenerative medicine. In particular, stem cells are a rich source of these soluble factors and MVs released from their surface may deliver RNA and microRNA into damaged organs. Based on these phenomena, we suggest that paracrine effects make major contributions in most of the currently reported positive results in clinical trials employing adult stem cells. We will also present possibilities for how these paracrine mechanisms could be exploited in regenerative medicine to achieve better therapeutic outcomes. This approach may yield critical improvements in current cell therapies before true pluripotent stem cells isolated in sufficient quantities from adult tissues and successfully expanded ex vivo will be employed in the clinic.
We present 1201 galaxies at 0.05 < z < 0.45 that host tidal features in the first ∼200 deg2 of imaging from the Hyper Suprime-Cam Subaru Strategic Program (HSC-SSP). We select these galaxies from a ...sample of 21,208 galaxies with spectroscopic redshifts drawn from the Sloan Digital Sky Survey (SDSS) spectroscopic campaigns. Of these galaxies, we identify 214 shell systems and 987 stream systems. For 575 of these systems, we are additionally able to measure the (g−i) colors of the tidal features. We find evidence for star formation in a subset of the streams, with the exception of streams around massive ellipticals, and find that stream host galaxies span the full range of stellar masses in our sample. Galaxies that host shells are predominantly red and massive: we find that observable shells form more frequently around ellipticals than around disk galaxies of the same stellar mass. Although the majority of the shells in our sample are consistent with being formed by minor mergers, 15% 4.4% of shell host galaxies have (g−i) colors as red as their host galaxy, consistent with being formed by major mergers. These "red shell" galaxies are preferentially aligned with the major axis of the host galaxy, as previously predicted from simulations. We suggest that although the bulk of the observable shell population originates from fairly minor mergers, which preferentially form shells that are not aligned with the major axis of the galaxy, major mergers produce a significant number of observable shells.
Objective
To investigate miR‐155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).
Methods
NanoString microRNA, microglia and immune gene profiles, protein ...mass spectrometry, and RNA‐seq analyses were measured in spinal cord microglia, splenic monocytes, and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR‐155 was targeted by genetic ablation or by peripheral or centrally administered anti–miR‐155 inhibitor in SOD1 mice.
Results
In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR‐155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and Mafb, and the upstream regulators Csf1r, Tgfb1, and Tgfbr1, which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR‐155 increased survival in SOD1 mice by 51 days in females and 27 days in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes, including Apoe in microglia. Treatment of adult microglia with apolipoprotein E suppressed the M0‐homeostatic unique microglia signature and induced an M1‐like phenotype. miR‐155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1G93A/miR‐155−/− mice. Intraventricular anti–miR‐155 treatment derepressed microglial miR‐155 targeted genes, and peripheral anti–miR‐155 treatment prolonged survival.
Interpretation
We found overexpression of miR‐155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR‐155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR‐155 as a therapeutic target for the treatment of ALS. ANN NEUROL 2015;77:75–99
OCT4 is a master transcriptional regulator, which mediates pluripotency in ESCs through inhibition of tissue-specific and promotion of stem cell-specific genes. Suppression of OCT4, along with other ...regulators of pluripotency, such as SOX2 and NANOG, has been correlated with cell-fate specification and lineage-specific differentiation. Recent reports have shown the expression of OCT4 in adult MSCs but have not ascribed functional homology with ESCs. MSCs are mesoderm-derived cells, primarily resident in adult bone marrow, that undergo lineage-specific differentiation to generate specialized cells such as stroma, fat, bone, and cartilage. We have previously demonstrated the plasticity of MSCs through their ability to generate neuronal cells. Here, we show that OCT4 provides similar regulatory circuitries in human MSCs and ESCs, using chromatin immunoprecipitation-DNA selection and ligation technology and loss-of-function studies. MSCs were found to express the embryonic transcription factors OCT4, NANOG, and SOX2. In addition, OCT4 was found to (a) target similar genes in MSCs and ESCs, (b) promote the expression of MSC-specific genes, and (c) regulate MSC cell cycle progression. The results suggest similar regulatory mechanisms for OCT4 in MSCs and ESCs and have implications regarding MSC plasticity. Disclosure of potential conflicts of interest is found at the end of this article.
Glioblastoma multiforme (GBM), the most common and lethal tumor of the adult brain, generally shows chemo- and radioresistance. MicroRNAs (miRs) regulate physiological processes, such as resistance ...of GBM cells to temozolomide (TMZ). Although miRs are attractive targets for cancer therapeutics, the effectiveness of this approach requires targeted delivery. Mesenchymal stem cells (MSCs) can migrate to the sites of cancers, including GBM. We report on an increase in miR-9 in TMZ-resistant GBM cells. miR-9 was involved in the expression of the drug efflux transporter, P-glycoprotein. To block miR-9, methods were developed with Cy5-tagged anti-miR-9. Dye-transfer studies indicated intracellular communication between GBM cells and MSCs. This occurred by gap junctional intercellular communication and the release of microvesicles. In both cases, anti-miR-9 was transferred from MSCs to GBM cells. However, the major form of transfer occurred with the microvesicles. The delivery of anti-miR-9 to the resistant GBM cells reversed the expression of the multidrug transporter and sensitized the GBM cells to TMZ, as shown by increased cell death and caspase activity. The data showed a potential role for MSCs in the functional delivery of synthetic anti-miR-9 to reverse the chemoresistance of GBM cells.
Bone marrow (BM) metastasis of breast cancer (BC) can recur even decades after initial diagnosis and treatment, implying the long-term survival of disseminated cancer cells in a dormant state. Here ...we investigated the role of microRNAs (miRNA) transmitted from BM stroma to BC cells via gap junctions and exosomes in tumor cell quiescence. MDA-MB-231 and T47D BC cells arrest in G(0) phase of the cell cycle when cocultured with BM stroma. Analyses of miRNA expression profiles identified numerous miRNAs implicated in cell proliferation including miR-127, -197, -222, and -223 targeting CXCL12. Subsequently, we showed that these CXCL12-specific miRNAs are transported from BM stroma to BC cells via gap junctions, leading to reduced CXCL12 levels and decreased proliferation. Stroma-derived exosomes containing miRNAs also contributed to BC cell quiescence, although to a lesser degree than miRNAs transmitted via gap junctions. This study shows that the transfer of miRNAs from BM stroma to BC cells might play a role in the dormancy of BM metastases.
Stereotypic behavior is an important indicator of compromised welfare. Zoo elephants are documented to perform stereotypic behavior, but the factors that contribute to performance have not been ...systematically assessed. We collected behavioral data on 89 elephants (47 African Loxodonta africana, 42 Asian Elephas maximus) at 39 North American zoos during the summer and winter. Elephants were videoed for a median of 12 daytime hours per season. A subset of 32 elephants (19 African, 13 Asian) was also observed live for a median of 10.5 nighttime hours. Percentages of visible behavior scans were calculated from five minute instantaneous samples. Stereotypic behavior was the second most commonly performed behavior (after feeding), making up 15.5% of observations during the daytime and 24.8% at nighttime. Negative binomial regression models fitted with generalized estimating equations were used to determine which social, housing, management, life history, and demographic variables were associated with daytime and nighttime stereotypic behavior rates. Species was a significant risk factor in both models, with Asian elephants at greater risk (daytime: p<0.001, Risk Ratio = 4.087; nighttime: p<0.001, Risk Ratio = 8.015). For both species, spending time housed separately (p<0.001, Risk Ratio = 1.009), and having experienced inter-zoo transfers (p<0.001, Risk Ratio = 1.175), increased the risk of performing higher rates of stereotypy during the day, while spending more time with juvenile elephants (p<0.001, Risk Ratio = 0.985), and engaging with zoo staff reduced this risk (p = 0.018, Risk Ratio = 0.988). At night, spending more time in environments with both indoor and outdoor areas (p = 0.013, Risk Ratio = 0.987) and in larger social groups (p = 0.039, Risk Ratio = 0.752) corresponded with reduced risk of performing higher rates of stereotypy, while having experienced inter-zoo transfers (p = 0.033, Risk Ratio = 1.115) increased this risk. Overall, our results indicate that factors related to the social environment are most influential in predicting elephant stereotypic behavior rates.
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