Single-cell atlas reveals meningeal leukocyte heterogeneity in the developing mouse brain
Aura ZelcoVanja BörjessonJurrian K. de KanterCristina Lebrero‐FernándezVolker M. LauschkeEridan Rocha‐FerreiraGisela NilssonSyam NairPernilla SvedinMats BemarkHenrik HagbergCarina MallardFrank C. P. HolstegeXiaoyang Wang
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Abstract:
The meninges are important for brain development and pathology. Using single-cell RNA sequencing, we have generated the first comprehensive transcriptional atlas of neonatal mouse meningeal leukocytes under normal conditions and after perinatal brain injury. We identified almost all known leukocyte subtypes and found differences between neonatal and adult border-associated macrophages, thus highlighting that neonatal border-associated macrophages are functionally immature with regards to immune responses compared with their adult counterparts. We also identified novel meningeal microglia-like cell populations that may participate in white matter development. Early after the hypoxic–ischemic insult, neutrophil numbers increased and they exhibited increased granulopoiesis, suggesting that the meninges are an important site of immune cell expansion with implications for the initiation of inflammatory cascades after neonatal brain injury. Our study provides a single-cell resolution view of the importance of meningeal leukocytes at the early stage of development in health and disease.Keywords:
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Abstract Normally, neutrophil pools are maintained by “steady-state” granulopoiesis. Inflammation, however, is thought to elicit growth factors that accelerate neutrophil production through a distinct developmental program known as “emergency” granulopoiesis. In IL-1RI-/- mice, adjuvant-induced emergency granulopoiesis is defective due to impaired progenitor proliferation. Interestingly, this hematopoietic defect is associated with impaired neutrophil mobilization from bone marrow (BM), raising the possibility that increased proliferation by hematopoietic progenitors is a response to reduced BM neutrophil density rather than pro-inflammatory signals. Consistent with this potential feedback mechanism, non-inflammatory depletions of mature BM neutrophils by passive antibody elicit emergency granulopoietic responses similar to those induced by adjuvant, and progenitor proliferation fluctuates inversely with BM neutrophil numbers. Furthermore, mice bearing a genetic defect in neutrophil survival exhibit constitutive emergency granulopoiesis. Whereas adjuvant potently induces serum G-CSF, a neutrophil growth and mobilization factor, neutrophil depletion elicits equally robust granulopoietic responses with substantially reduced levels of G-CSF. These observations suggest that other - perhaps unknown - factors mediate accelerated granulopoiesis, and we propose a common model for the feedback regulation of both steady-state and emergency granulopoiesis.
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