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Project description:Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and ultimate fate of disease-associated microglia (DAM) remains largely unknown. We established a lineage tracing system, leveraging the expression dynamics of Spp1, which allows for genetic labeling of DAM-like microglia and tracking their behavior during brain injury and recovery. Fate-mapping of Spp1+ microglia in juvenile stroke revealed an irreversible state of reactive microglia that are ultimately eliminated from the injured brain. In contrast, DAM-like microglia in the neonatal context exhibit high plasticity, capable of regaining a homeostatic signature and integrating into the global microglial network after recovery. Furthermore, neonatal injury has a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, by unraveling the fate of DAM-like microglia in various neuropathological conditions, our work highlights the exceptional plasticity and innate immune memory of neonatal microglia.
2024-01-24 | GSE247391 | GEO
Project description:Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and ultimate fate of disease-associated microglia (DAM) remains largely unknown. We established a lineage tracing system, leveraging the expression dynamics of Spp1, which allows for genetic labeling of DAM-like microglia and tracking their behavior during brain injury and recovery. Fate-mapping of Spp1+ microglia in juvenile stroke revealed an irreversible state of reactive microglia that are ultimately eliminated from the injured brain. In contrast, DAM-like microglia in the neonatal context exhibit high plasticity, capable of regaining a homeostatic signature and integrating into the global microglial network after recovery. Furthermore, neonatal injury has a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, by unraveling the fate of DAM-like microglia in various neuropathological conditions, our work highlights the exceptional plasticity and innate immune memory of neonatal microglia.
2024-01-24 | GSE247390 | GEO
Project description:Whether monocytes contribute to the brain microglial pool in development or after brain injury remains contentious. To address this issue, we generated CCR2-CreER mice to track monocyte derivatives in a tamoxifen-inducible manner. This method labeled Ly6Chi and Ly6Clo monocytes after tamoxifen dosing and detected a surge of perivascular macrophages before blood-brain barrier breakdown in adult stroke. When dosed by tamoxifen at embryonic day 17 (E17), this method captured fetal hematopoietic cells at E18, subdural Ki67+ ameboid cells at postnatal day 2 (P2), and perivascular microglia, leptomeningeal macrophages, and Iba1+Tmem119+P2RY12+ parenchymal microglia in selective brain regions at P24. Furthermore, this fate mapping strategy revealed an acute influx of monocytes after neonatal stroke, which gradually transformed into a ramified morphology and expressed microglial marker genes (Sall1, Tmem119, and P2RY12) for at least 62 days after injury. These results suggest an underappreciated level of monocyte-to-microglia transition in development and after neonatal stroke.
| S-EPMC7449686 | biostudies-literature
Project description:Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
| S-EPMC3719181 | biostudies-literature
Project description:BACKGROUND:Neuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE). Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states. However, the effects of microglial depletion on neonatal HIE remain unclear. METHODS:Tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ (microglia-depleted model) and Cx3cr1CreER/+Rosa26DTA/- (control) mice at P8 and P9 to assess the effect of microglial depletion. The density of microglia was quantified using Iba-1 staining. Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis. At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10. The infarct size and apoptotic cells were analyzed at P13. Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13. RESULTS:At P10, tamoxifen administration induced >?99% microglial depletion in DTA+ mice. Following HI insult, there was persisted microglial depletion over 97% at P13. Compared to male DTA- mice, male DTA+ mice exhibited significantly larger infarct volumes; however, there were no significant differences among females. Moreover, compared to male DTA- mice, male DTA+ mice had a significantly higher density of TUNEL+ cells in the caudoputamen, cerebral cortex, and thalamus. Moreover, compared to female DTA- mice, female DTA+ mice showed a significantly greater number of TUNEL+ cells in the hippocampus and thalamus. Compared to DTA- mice, ELISA revealed significantly lower IL-10 and TGF-? levels in both male and female DTA+ mice under both normal conditions and after HI (more pronounced). CONCLUSION:We established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males.
| S-EPMC7149909 | biostudies-literature
Project description:We performed a single-cell transcriptomic analysis of monocyte and monocyte progenitors by single-cell mRNA sequencing (scRNA-seq) using the C1 Fluidigm platform. We sorted BM cMoPs (Lin−CD117+CD115+CD135−Ly6C+), BM Ly6C+ monocytes (Lin−CD117-CD115+CD135−Ly6C+) and blood Ly6Chi monocytes (CD115+CD11b+Ly6Chi) from wild-type (WT) C57BL/6 mice by fluorescence-activated cell sorting (FACS) and generated transcriptional profiles for each individual cell (n = 38 for blood Ly6Chi monocytes, n = 66 for BM cMoPs, n = 57 for BM Ly6C+ monocytes).
2019-08-19 | GSE134523 | GEO
Project description:BackgroundThe binding of the T cell receptor (TCR) to major histocompatibility complex (MHC) molecules in the thymus determines fates of TCRalphabeta lymphocytes that subsequently home to secondary lymphoid tissue. TCR transgenic models have been used to study thymic selection and lineage commitment. Most TCR transgenic mice express the rearranged TCRalphabeta prematurely at the double negative stage and abnormal TCRalphabeta populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice.Methodology and principal findingsTo determine developmental pathways of TCR-transgenic thymocytes, we used Cre-LoxP-mediated fate mapping and show here that premature expression of a transgenic TCRalphabeta diverts some developing thymocytes to a developmental pathway which resembles that of gamma delta cells. We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORgammat-positive CD4(+)8(+) (double positive, DP) stage to accumulate either as CD4(-)8(-) (double negative, DN) or as CD8alpha(+) T cells in lymph nodes or gut epithelium. Likewise, DN TCRalphabeta cells in lymphoid tissue of female mice were not derived from DP thymocytes.ConclusionThe results further support the hypothesis that the premature expression of the TCRalphabeta can divert DN thymocytes into gamma delta lineage cells.
| S-EPMC2211402 | biostudies-literature
Project description:Rationale: Monocytes belong to the mononuclear phagocyte system and are immune responders to tissue injury and infection. There were also reports of monocytes transforming to microglia-like cells. Here we explore the roles of monocytes in microglia ontogeny and the pathogenesis of neonatal cerebral hypoxic-ischemic (HI) brain injury in mice. Methods: We used three genetic methods to track the development of monocytes, including CX3CR1GFP/+; CCR2RFP/+ reporter mice, adoptive transfer of GFP+ monocytes, and fate-mapping with CCR2-CreER mice, in neonatal mouse brains with or without lipopolysaccharide (LPS, 0.3 mg/kg)-sensitized Vannucci HI. We also used genetic (CCR2RFP/ RFP, CCR2 knockout) and pharmacological methods (RS102895, a CCR2 antagonist) to test the roles of monocytic influx in LPS/HI brain injury. Results: CCR2+ monocytes entered the late-embryonic brains via choroid plexus, but rapidly became CX3CR1+ amoeboid microglial cells (AMCs). The influx of CCR2+ monocytes declined after birth, but recurred after HI or LPS-sensitized HI (LPS/HI) brain injury, particularly in the hippocampus. The CCR2-CreER-based fate-mapping showed that CCR2+ monocytes became CD68+ TNFα+ macrophages within 4 d after LPS/HI, and maintained as TNFα+ MHCII+ macrophages or persisted as Tmem119+ Sall1+ P2RY12+ ramified microglia for at least five months after injury. Genetic deletion of the chemokine receptor CCR2 markedly diminished monocytic influx, the expression of pro- and anti-inflammatory cytokines, and brain damage. Post-LPS/HI application of RS102895 also reduced inflammatory responses and brain damage, leading to better cognitive functions. Conclusion: These results suggest that monocytes promote acute inflammatory responses and may become pathological microglia long after the neonatal LPS/HI insult. Further, blocking the influx of monocytes may be a potential therapy for neonatal brain injury.
| S-EPMC8692901 | biostudies-literature
Project description:Cell fate maps describe how the sequence of cell division, migration, and apoptosis transform a zygote into an adult. Yet, it is only in Caenorhabditis elegans where microscopic observation of each cell division has allowed for construction of a complete fate map. More complex, and opaque, animals prove less yielding. DNA replication, however, generates somatic mutations. Consequently, multicellular organisms comprise mosaics where most cells acquire unique genomes that are potentially capable of delineating their ancestry. Here we take a phylogenetic approach to passively retrace embryonic relationships by deducing the order in which mutations have arisen during development. We show that polyguanine repeat DNA sequences are particularly useful genetic markers, because they frequently change length during mitosis. To demonstrate feasibility, we phylogenetically reconstruct the lineage of cultured mouse NIH 3T3 cells based on mutations affecting the length of polyguanine markers. We then employ whole genome amplification to genotype polyguanine markers in single cells taken from a mouse and use phylogenetics to infer the developmental relationships of the sampled tissues. The result is consistent with the present understanding of embryogenesis and demonstrates the large scale potential of this method for producing a complete mammalian cell fate at the resolution of a single cell.
| S-EPMC1414797 | biostudies-literature
Project description:The recent paradigm shift that microglia are yolk sac-derived, not hematopoietic-derived, is reshaping our knowledge about the isolated role of microglia in CNS diseases, including degenerative conditions of the retina. However, unraveling microglial-specific functions has been hindered by phenotypic overlap of microglia with monocyte-derived macrophages. The latter are differentiated from recruited monocytes in neuroinflammation, including retina. Here we demonstrate the use of fate mapping wherein microglia and monocyte-derived cells are endogenously labeled with different fluorescent reporters. Combining this method with 12-color flow cytometry, we show that these two populations are definitively distinguishable by phenotype in retina. We prove that retinal microglia have a unique CD45(lo) CD11c(lo) F4/80(lo) I-A/I-E(-) signature, conserved in the steady state and during retinal injury. The latter was observed in the widely used light-induced retinal degeneration model and corroborated in other models, including whole-body irradiation/bone-marrow transplantation. The literature contains conflicting observations about whether microglia, including in the retina, increase expression of these markers in neuroinflammation. We show that monocyte-derived macrophages have elevated expression of these surface markers, not microglia. Our resolution of such phenotypic differences may serve as a robust way to help characterize isolated roles of these cells in retinal neuroinflammation and possibly elsewhere in CNS.
| S-EPMC4746646 | biostudies-literature