Generation and external validation of a histological transformation risk model for patients with follicular lymphoma.

Follicular lymphoma (FL) is the most frequent indolent lymphoma. 10-15% of patients suffer histological transformation (HT) to a more aggressive lymphoma, usually diffuse large B cell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis. We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n = 104, 62 from non-transformed, and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve. The clinicogenetic nomogram included the mutational status of three genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk FLIPI and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs. 0.51 in the high-risk group and, at 60 months, 0.69 vs. 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs. 0.54 in the high-risk group at 24 months, and 0.71 vs. 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (FLIPI) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation.

A genetic profiling guideline to support diagnosis and clinical management of lymphomas.

The new lymphoma classifications (International Consensus Classification of Mature Lymphoid Neoplasms, and 5th World Health Organization Classification of Lymphoid Neoplasms) include genetics as an integral part of lymphoma diagnosis, allowing better lymphoma subclassification, patient risk stratification, and prediction of treatment response. Lymphomas are characterized by very few recurrent and disease-specific mutations, and most entities have a heterogenous genetic landscape with a long tail of recurrently mutated genes. Most of these occur at low frequencies, reflecting the clinical heterogeneity of lymphomas. Multiple studies have identified genetic markers that improve diagnostics and prognostication, and next-generation sequencing is becoming an essential tool in the clinical laboratory. This review provides a "next-generation sequencing" guide for lymphomas. It discusses the genetic alterations of the most frequent mature lymphoma entities with diagnostic, prognostic, and predictive potential and proposes targeted sequencing panels to detect mutations and copy-number alterations for B- and NK/T-cell lymphomas.

Developing One Health surveillance systems.

The health of humans, domestic and wild animals, plants, and the environment are inter-dependent. Global anthropogenic change is a key driver of disease emergence and spread and leads to biodiversity loss and ecosystem function degradation, which are themselves drivers of disease emergence. Pathogen spill-over events and subsequent disease outbreaks, including pandemics, in humans, animals and plants may arise when factors driving disease emergence and spread converge. One Health is an integrated approach that aims to sustainably balance and optimize human, animal and ecosystem health. Conventional disease surveillance has been siloed by sectors, with separate systems addressing the health of humans, domestic animals, cultivated plants, wildlife and the environment. One Health surveillance should include integrated surveillance for known and unknown pathogens, but combined with this more traditional disease-based surveillance, it also must include surveillance of drivers of disease emergence to improve prevention and mitigation of spill-over events. Here, we outline such an approach, including the characteristics and components required to overcome barriers and to optimize an integrated One Health surveillance system.

A deep transcriptome meta-analysis reveals sex differences in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS), a chronic auto-immune, inflammatory, and degenerative disease of the central nervous system, affects both males and females; however, females suffer from a higher risk of developing MS (2-3:1 ratio relative to males). The precise sex-based factors influencing risk of MS are currently unknown. Here, we explore the role of sex in MS to identify molecular mechanisms underlying observed MS sex differences that may guide novel therapeutic approaches tailored for males or females. METHODS: We performed a rigorous and systematic review of genome-wide transcriptome studies of MS that included patient sex data in the Gene Expression Omnibus and ArrayExpress databases following PRISMA statement guidelines. For each selected study, we analyzed differential gene expression to explore the impact of the disease in females (IDF), in males (IDM) and our main goal: the sex differential impact of the disease (SDID). Then, for each scenario (IDF, IDM and SDID) we performed 2 meta-analyses in the main tissues involved in the disease (brain and blood). Finally, we performed a gene set analysis in brain tissue, in which a higher number of genes were dysregulated, to characterize sex differences in biological pathways. RESULTS: After screening 122 publications, the systematic review provided a selection of 9 studies (5 in blood and 4 in brain tissue) with a total of 474 samples (189 females with MS and 109 control females; 82 males with MS and 94 control males). Blood and brain tissue meta-analyses identified, respectively, 1 (KIR2DL3) and 13 (ARL17B, CECR7, CEP78, IFFO2, LOC401127, NUDT18, RNF10, SLC17A5, STMP1, TRAF3IP2-AS1, UBXN2B, ZNF117, ZNF488) MS-associated genes that differed between males and females (SDID comparison). Functional analyses in the brain revealed different altered immune patterns in females and males (IDF and IDM comparisons). The pro-inflammatory environment and innate immune responses related to myeloid lineage appear to be more affected in females, while adaptive responses associated with the lymphocyte lineage in males. Additionally, females with MS displayed alterations in mitochondrial respiratory chain complexes, purine, and glutamate metabolism, while MS males displayed alterations in stress response to metal ion, amine, and amino acid transport. CONCLUSION: We found transcriptomic and functional differences between MS males and MS females (especially in the immune system), which may support the development of new sex-based research of this disease. Our study highlights the importance of understanding the role of biological sex in MS to guide a more personalized medicine.

Caso autóctono de rickettsiosis por Rickettsia parkeri en la Selva Paranaense, Misiones, Argentina / Autochthonous Rickettsia parkeri rickettsiosis in the Paranaense Forest, Misiones, Argentina

Resumen Se informa un caso autóctono de rickettsiosis por Rickettsia parkeri, ocurrido en junio del 2018 en la zona selvática del Parque Provincial Urugua-í, Misiones, Argentina, región sin registros previos de esta enfermedad en humanos. Se describen los aspectos epidemiológicos, ecológicos, clínicos y de laboratorio necesarios para el diagnóstico oportuno y el tratamiento adecuado. Se resalta el hecho de considerar a las rickettsiosis como diagnóstico diferencial ante un paciente con síndrome febril agudo exantemático; el antecedente epidemiológico de exposición al vector característico de la región, garrapatas del género Amblyomma, es un elemento fundamental.

Abstract We report an autochthonous case of Rickettsia parkeri rickettsiosis occurred in June 2018 in a forested area of the Urugua-í Provincial Park, Misiones, Argentina. No previous records of this disease in humans have been previously reported in this region. The epidemiological, ecological, clinical, and laboratory features required for a proper diagnosis and adequate treatment are described here. The fact of considering rickettsiosis as a differential diagnosis in a patient with exanthematic acute febrile syndrome is highlighted, being the epidemiological history of exposure to the vector (ticks of the genus Amblyomma) an essential element.

[Autochthonous Rickettsia parkeri rickettsiosis in the Paranaense Forest, Misiones, Argentina]. / Caso autóctono de rickettsiosis por Rickettsia parkeri en la Selva Paranaense, Misiones, Argentina.

We report an autochthonous case of Rickettsia parkeri rickettsiosis occurred in June 2018 in a forested area of the Urugua-í Provincial Park, Misiones, Argentina. No previous records of this disease in humans have been previously reported in this region. The epidemiological, ecological, clinical, and laboratory features required for a proper diagnosis and adequate treatment are described here. The fact of considering rickettsiosis as a differential diagnosis in a patient with exanthematic acute febrile syndrome is highlighted, being the epidemiological history of exposure to the vector (ticks of the genus Amblyomma) an essential element.

Monitoring of Circulating Tumor DNA Predicts Response to Treatment and Early Progression in Follicular Lymphoma: Results of a Prospective Pilot Study.

PURPOSE: Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL. EXPERIMENTAL DESIGN: We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples. RESULTS: Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients. CONCLUSIONS: Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.

Unveiling the Role of the Tumor Microenvironment in the Treatment of Follicular Lymphoma.

Follicular lymphomas (FL) are neoplasms that resemble normal germinal center (GC) B-cells. Normal GC and neoplastic follicles contain non-neoplastic cells such as T-cells, follicular dendritic cells, cancer associated fibroblasts, and macrophages, which define the tumor microenvironment (TME), which itself is an essential factor in tumor cell survival. The main characteristics of the TME in FL are an increased number of follicular regulatory T-cells (Treg) and follicular helper T-cells (Tfh), M2-polarization of macrophages, and the development of a nodular network by stromal cells that creates a suitable niche for tumor growth. All of them play important roles in tumor angiogenesis, inhibition of apoptosis, and immune evasion, which are key factors in tumor progression and transformation risk. Based on these findings, novel therapies have been developed to target specific mutations present in the TME cells, restore immune suppression, and modulate TME.

Emerging hantaviruses in Central Argentina: First case of Hantavirus Pulmonary Syndrome caused by Alto Paraguay virus, and a novel orthohantavirus in Scapteromys aquaticus rodent.

Orthohantaviruses are emerging rodent-borne pathogens that cause Hantavirus Pulmonary Syndrome in humans. They have a wide range of rodent reservoir hosts and are transmitted to humans through aerosolized viral particles generated by the excretions of infected individuals. Since the first description of HPS in Argentina, new hantaviruses have been reported throughout the country, most of which are pathogenic to humans. We present here the first HPS case infected with Alto Paraguay virus reported in Argentina. Until now, Alto Paraguay virus was considered a non-pathogenic orthohantavirus since it was identified in a rodent, Holochilus chacarius. In addition to this, with the goal of identifying potential hantavirus host species in the province of Santa Fe, we finally describe a novel orthohantavirus found in the native rodent Scapteromys aquaticus, which differed from other hantaviruses described in the country so far. Our findings implicate an epidemiological warning regarding these new orthohantaviruses circulating in Central Argentina as well as new rodent species that must be considered as hosts from now on.

High-fat diet alters stress behavior, inflammatory parameters and gut microbiota in Tg APP mice in a sex-specific manner.

Long-term high-fat diet (HFD) consumption commonly leads to obesity, a major health concern of western societies and a risk factor for Alzheimer's disease (AD). Both conditions present glial activation and inflammation and show sex differences in their incidence, clinical manifestation, and disease course. HFD intake has an important impact on gut microbiota, the bacteria present in the gut, and microbiota dysbiosis is associated with inflammation and certain mental disorders such as anxiety. In this study, we have analyzed the effects of a prolonged (18 weeks, starting at 7 months of age) HFD on male and female mice, both wild type (WT) and TgAPP mice, a model for AD, investigating the behavioral profile, gut microbiota composition and inflammatory/phagocytosis-related gene expression in hippocampus. In the open-field test, no overt differences in motor activity were observed between male and female or WT and TgAPP mice on a low-fat diet (LFD). However, HFD induced anxiety, as judged by decreased motor activity and increased time in the margins in the open-field, and a trend towards increased immobility time in the tail suspension test, with increased defecation. Intriguingly, female TgAPP mice on HFD showed less immobility and defecation compared to female WT mice on HFD. HFD induced dysbiosis of gut microbiota, resulting in reduced microbiota diversity and abundance compared with LFD fed mice, with some significant differences due to sex and little effect of genotype. Gene expression of pro-inflammatory/phagocytic markers in the hippocampus were not different between male and female WT mice, and in TgAPP mice of both sexes, some cytokines (IL-6 and IFNγ) were higher than in WT mice on LFD, more so in female TgAPP (IL-6). HFD induced few alterations in mRNA expression of inflammatory/phagocytosis-related genes in male mice, whether WT (IL-1ß, MHCII), or TgAPP (IL-6). However, in female TgAPP, altered gene expression returned towards control levels following prolonged HFD (IL-6, IL-12ß, TNFα, CD36, IRAK4, PYRY6). In summary, we demonstrate that HFD induces anxiogenic symptoms, marked alterations in gut microbiota, and increased expression of inflammatory genes, except for female TgAPP that appear to be resistant to the diet effects. Lifestyle interventions should be introduced to prevent AD onset or exacerbation by reducing inflammation and its associated symptoms; however, our results suggest that the eventual goal of developing prevention and treatment strategies should take sex into consideration.

An Overview on Diffuse Large B-Cell Lymphoma Models: Towards a Functional Genomics Approach.

Lymphoma research is a paradigm of the integration of basic and clinical research within the fields of diagnosis and therapy. Clinical, phenotypic, and genetic data are currently used to predict which patients could benefit from standard treatment. However, alternative therapies for patients at higher risk from refractoriness or relapse are usually empirically proposed, based on trial and error, without considering the genetic complexity of aggressive B-cell lymphomas. This is primarily due to the intricate mosaic of genetic and epigenetic alterations in lymphomas, which are an obstacle to the prediction of which drug will work for any given patient. Matching a patient's genes to drug sensitivity by directly testing live tissues comprises the "precision medicine" concept. However, in the case of lymphomas, this concept should be expanded beyond genomics, eventually providing better treatment options for patients in need of alternative therapeutic approaches. We provide an overview of the most recent findings in diffuse large B-cell lymphomas genomics, from the classic functional models used to study tumor biology and the response to experimental treatments using cell lines and mouse models, to the most recent approaches with spheroid/organoid models. We also discuss their potential relevance and applicability to daily clinical practice.

Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6 years. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, and CD58 had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and BCL2 and BCL6 translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N12-S, EZB2-S, MCD2-S, BN22-S, and ST22-S groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST22-S is the group with the best clinical outcome and N12-S, the more aggressive one. EZB2-S identified a subgroup with a worse prognosis among GCB-DLBLC cases.

Aging and sex: Impact on microglia phagocytosis.

Microglia dysfunction and activation are important hallmarks of the aging brain and are concomitant with age-related neurodegeneration and cognitive decline. Age-associated changes in microglia migration and phagocytic capacity result in maladaptive responses, chronic neuroinflammation, and worsened outcomes in neurodegenerative disorders. Given the sex bias in the incidence, prevalence, and therapy response of most neurological disorders, we have here examined whether the phagocytic activity of aged microglia is different in males and females. With this aim, the phagocytosis activity of male and female cells was compared in an in vitro aged microglia model and in microglia isolated from adult (5-month-old) or aged (18-month-old) mice. In both models, the phagocytosis of neural debris increased with aging in male and female cells and was higher in aged female microglia than in aged male cells. However, female aged microglia lost its ability to adapt its phagocytic activity to inflammatory conditions. These findings suggest that microglia phagocytosis of neural debris may represent a previously unexplored neuroprotective characteristic of aged microglia that may contribute to the generation of sex differences in the manifestation of neurodegenerative diseases.

Performance of rapid tests for canine visceral leishmaniasis diagnosis in Argentina.

To diagnose dogs infected by Leishmania infantum rK39 rapid diagnosis test is widely used in the Americas, while dual path platform (DPP) was recently adopted by Brazil. In this study we assessed the performance of rK39-RDT and DPP tests in recent urban transmission scenarios of Argentina. The sensitivity and specificity were evaluated with a sera panel and field samples, taken as true infected those from parasitological and/or PCR positive tests. Since none of these tests can be taken as a gold standard, the performance was also evaluated using Latent Class Analysis, a statistical modeling technique which allows to estimating sensitivity and specificity defining a latent class variable as the reference standard. The sensitivity of both tests in the panel was around 92% (symptomatic dogs 96%, asymptomatic 83%), while the sensitivity in field samples of rK39-RDT was 77%, and DPP 98% (mean in symptomatic dogs 89%, asymptomatic 82%). The specificity was similar for both tests and samples, around 98%. Therefore, these tests are acceptable for program dog population-based studies, as spatial stratification, focus intervention and follow up, and they could be used for individual screening and confirmation of clinical presumptive diagnosis in polysymptomatic dogs. The inability to discriminate between immunity and actual infectiousness suggest that a combination with other non-immunological based tests will be required for highly sensitive/specific diagnosis in order to targeting control measures in individual reservoirs from public health perspective, as for individual management from animal health perspective.

Para diagnosticar perros infectados por Leishmania infantum, en las Américas se utiliza ampliamente la prueba rápida rK39, mientras que DPP fue adoptado recientemente por Brasil. En este estudio se evaluó el desempeño de las pruebas rK39-RDT y DPP en escenarios de transmisión urbana reciente en Argentina. La sensibilidad y especificidad se evaluaron con un panel de sueros y muestras de campo, considerando muestras infectadas verdaderas aquellas con pruebas parasitológicas y/o de PCR positivas. Como ninguna de estas pruebas puede considerarse estándar de oro, el desempeño también se evaluó mediante análisis de clases latentes, una técnica de modelado estadístico que permite estimar sensibilidad y especificidad definiendo una variable de clase latente como estándar. La sensibilidad de ambas pruebas en el panel fue de alrededor del 92% (perros sintomáticos 96%, asintomáticos 83%), mientras que la sensibilidad en muestras de campo fue rK39-RDT: 77%, y DPP 98% (media en perros sintomáticos 89%, asintomáticos 82%). La especificidad fue similar para ambas pruebas y muestras, cerca de 98%. Por lo tanto, estas pruebas son aceptables para estudios programáticos caninos de base-poblacional, como estratificación espacial, intervención de foco y seguimiento, y podrían utilizarse para el tamizaje individual y la confirmación del diagnóstico clínico presuntivo en perros poli-sintomáticos. La incapacidad de discriminar entre inmunidad e infectividad real sugiere que se requerirá una combinación con otras pruebas, de base no inmunológica, para un diagnóstico suficientemente sensible/específico que permita definir las medidas de control en reservorios individuales, tanto para salud pública, como para la gestión individual en salud animal.

Performance of rapid tests for canine visceral leishmaniasis diagnosis in Argentina

To diagnose dogs infected by Leishmania infantum rK39 rapid diagnosis test is widely used in the Americas, while dual path platform (DPP) was recently adopted by Brazil. In this study we assessed the performance of rK39-RDT and DPP tests in recent urban transmission scenarios of Argentina. The sensitivity and specificity were evaluated with a sera panel and field samples, taken as true infected those from parasitological and/or PCR positive tests. Since none of these tests can be taken as a gold standard, the performance was also evaluated using Latent Class Analysis, a statistical modeling technique which allows to estimating sensitivity and specificity defining a latent class variable as the reference standard. The sensitivity of both tests in the panel was around 92% (symptomatic dogs 96%, asymptomatic 83%), while the sensitivity in field samples of rK39-RDT was 77%, and DPP 98% (mean in symptomatic dogs 89%, asymptomatic 82%). The specificity was similar for both tests and samples, around 98%. Therefore, these tests are acceptable for program dog population-based studies, as spatial stratification, focus intervention and follow up, and they could be used for individual screening and confirmation of clinical presumptive diagnosis in polysymptomatic dogs. The inability to discriminate between immunity and actual infectiousness suggest that a combination with other non-immunological based tests will be required for highly sensitive/specific diagnosis in order to targeting control measures in individual reservoirs from public health perspective, as for individual management from animal health perspective.

Para diagnosticar perros infectados por Leishmania infantum, en las Américas se utiliza ampliamente la prueba rápida rK39, mientras que DPP fue adoptado recientemente por Brasil. En este estudio se evaluó el desempeño de las pruebas rK39-RDT y DPP en escenarios de transmisión urbana reciente en Argentina. La sensibilidad y especificidad se evaluaron con un panel de sueros y muestras de campo, considerando muestras infectadas verdaderas aquellas con pruebas parasitológicas y/o de PCR positivas. Como ninguna de estas pruebas puede considerarse estándar de oro, el desempeño también se evaluó mediante análisis de clases latentes, una técnica de modelado estadístico que permite estimar sensibilidad y especificidad definiendo una variable de clase latente como estándar. La sensibilidad de ambas pruebas en el panel fue de alrededor del 92% (perros sintomáticos 96%, asintomáticos 83%), mientras que la sensibilidad en muestras de campo fue rK39-RDT: 77%, y DPP 98% (media en perros sintomáticos 89%, asintomáticos 82%). La especificidad fue similar para ambas pruebas y muestras, cerca de 98%. Por lo tanto, estas pruebas son aceptables para estudios programáticos caninos de base-poblacional, como estratificación espacial, intervención de foco y seguimiento, y podrían utilizarse para el tamizaje individual y la confirmación del diagnóstico clínico presuntivo en perros poli-sintomáticos. La incapacidad de discriminar entre inmunidad e infectividad real sugiere que se requerirá una combinación con otras pruebas, de base no inmunológica, para un diagnóstico suficientemente sensible/específico que permita definir las medidas de control en reservorios individuales, tanto para salud pública, como para la gestión individual en salud animal.

Involvement of Wnt7a in the role of M2c microglia in neural stem cell oligodendrogenesis.

BACKGROUND: The participation of microglia in CNS development and homeostasis indicate that these cells are pivotal for the regeneration that occurs after demyelination. The clearance of myelin debris and the inflammatory-dependent activation of local oligodendrocyte progenitor cells in a demyelinated lesion is dependent on the activation of M2c microglia, which display both phagocytic and healing functions. Emerging interest has been raised about the role of Wnt/ß-catenin signaling in oligodendrogenesis and myelination. Besides, cytokines and growth factors released by microglia can control the survival, proliferation, migration, and differentiation of neural stem cells (NSCs), contributing to remyelination through the oligodendrocyte specification of this adult neurogenic niche. METHODS: TMEV-IDD model was used to study the contribution of dorsal SVZ stem cells to newly born oligodendrocytes in the corpus callosum following demyelination by (i) en-face dorsal SVZ preparations; (ii) immunohistochemistry; and (iii) cellular tracking. By RT-PCR, we analyzed the expression of Wnt proteins in demyelinated and remyelinating corpus callosum. Using in vitro approaches with microglia cultures and embryonic NSCs, we studied the role of purified myelin, Wnt proteins, and polarized microglia-conditioned medium to NSC proliferation and differentiation. One-way ANOVA followed by Bonferroni's post-hoc test, or a Student's t test were used to establish statistical significance. RESULTS: The demyelination caused by TMEV infection is paralleled by an increase in B1 cells and pinwheels in the dorsal SVZ, resulting in the mobilization of SVZ proliferative progenitors and their differentiation into mature oligodendrocytes. Demyelination decreased the gene expression of Wnt5a and Wnt7a, which was restored during remyelination. In vitro approaches show that Wnt3a enhances NSC proliferation, while Wnt7a and myelin debris promotes oligodendrogenesis from NSCs. As phagocytic M2c microglia secrete Wnt 7a, their conditioned media was found to induce Wnt/ß-Catenin signaling in NSCs promoting an oligodendroglial fate. CONCLUSIONS: We define here the contribution of microglia to Wnt production depending on their activation state, with M1 microglia secreting the Wnt5a protein and M2c microglia secreting Wnt7a. Collectively, our data reveal the role of reparative microglia in NSC oligodendrogenesis with the involvement of Wnt7a.