Acta Neuropathologica Communications最新文献

Fibroblasts are a group of stromal cells that contribute to the scarring process in many neurological conditions in the central nervous system (CNS). Recently, single-cell sequencing efforts allowed an in-depth understanding of their cell origins and subpopulation profiles. Meanwhile, vascular leptomeningeal cells and the "type A pericytes" were also proposed as CNS fibroblast-like cells in the last decade by histological, functional and transcriptomic analysis. While these cells share overlapping features with CNS fibroblasts, the inconsistent use of nomenclature and partially overlapping cell-type markers is likely to cause confusion within the growing field of neurobiology. In this review, we will delineate the current knowledge of subtypes and functions of CNS fibroblasts, with special focus on the source of PVFs during development and the nomenclature origins of other similar cell types. We aim to provide comprehensive insights into these cells with similar functions or transcriptomic profiles.

The vast majority of tumours in the sellar region are pituitary neuroendocrine tumours, also called pituitary adenomas. Sellar gangliocytomas (GCs), benign tumours that originate from neuronal ganglionic cells, account for less than 1% of sellar tumours. Even rarer are mixed gangliocytoma-pituitary neuroendocrine tumours (GC-PitNET). These tumours are often associated with hormone hypersecretion, most commonly resulting in acromegaly. The histogenesis of mixed GC-PitNET is currently unclear. In this paper, we present comprehensive clinical, immunohistochemical, targeting enrichment next generation DNA sequencing, and genome-wide methylation data from four patients with mixed GC-PitNETs, three with acromegaly and one with Cushing's disease. Transcriptomic data are also included for two of the patients. Our findings indicate that mixed GC-PitNETs have different clinical course, with the acromegaly patients showing greater resistance to pharmacological therapy, as well as different protein expression and molecular features compared to respective pure PitNETs. The transcriptomic data on two patients with somatotroph GC-PitNET show involvement of mitochondrial and ribosomal genes, suggesting a distinct gene expression pattern, in comparison with pure somatotroph tumours. Furthermore, the expression pattern of selected stem cell markers, mainly SOX9, supports a common origin of the neuroendocrine and ganglionic tumour components, suggesting the involvement of stem cells in tumorigenesis.

Background: Meningiomas are the most common primary intracranial tumor in adults and systemic therapy is urgently needed for high-grade fatal tumors and those cannot be completely removed by surgery. Multiomics studies have established a molecular classification system in addition to the grading system by the World Health Organization, and SWI/SNF-related BAF chromatin remodeling complex subunit B1 (SMARCB1) mutation was enriched in the immunogenic subgroup. Meningiomas are myeloid-dominant tumors with abundant and unevenly distributed CD163⁺ macrophages, a feature linked to intratumoral heterogeneity. However, the biological drivers of this phenomenon remain unknown.

Methods: A study cohort consisting of 113 patients was established to examine the association between serum immune profile and relapse-free survival. The second study cohort containing 35 patients across different WHO grades and disease states was established to validate and identify immune cell infiltration in the tumor microenvironment. Spatial distribution of immune cells was accessed by immunohistochemistry staining and multiplex immunofluorescence staining. Single-cell RNA sequencing (RNA-seq), bulk RNA-seq and whole exon seq data were analyzed to identify genomic signatures that represent the immunogenic subgroup of meningiomas. Public databases were explored to determine a potential mechanistic link between SMARCB1 and the interleukin-17/colony stimulating factor 1 (IL-17/CSF1) axis.

Results: Serum IL-17 A and IL-5 levels favored a good prognosis of meningioma. CD163⁺ macrophages were enriched in meningiomas regardless of the WHO grade and disease status (primary or recurrent). Compared to CD25⁺/Foxp3⁺ regulatory T cells and CD15⁺/CD33⁺ myeloid-derived suppressor cells, CD163⁺ macrophages tend to be more enriched around SMARCB1-deficient tumor cells. RNA-seq revealed that a 14-gene signature, including IL-17, CSF1, and related upstream and downstream genes, accurately characterizes the immunogenic subtype of meningiomas.

Conclusion: The findings reveal that the infiltration of CD163⁺ macrophages in meningioma may be mediated by the IL-17/CSF1 axis through SMARCB1 regulation.

Lens epithelium-derived growth factor (LEDGF), encoded by the Psip1 gene, exists in two splice variants, LEDGF/p75 and LEDGF/p52. Although little is known about its role in the brain, LEDGF has been proposed to play a role in neurogenesis. Since known LEDGF binding partners, such as PogZ, CDA7L, MLL1 and MeCP2 are implicated in neurological dysfunction, we investigated the role of LEDGF in mouse brain. We developed a conditional Psip1 knock-out (cKO) mouse model by crossbreeding Psip1^fl/fl mice with Nestin^Cre mice, resulting in neuronal depletion of both isoforms in the central nervous system. In wild-type (WT) animals, brain region-dependent alternative splicing was evidenced, with more p75 over p52 in the cerebellum and more p52 over p75 in the hippocampus. Behavioral phenotyping revealed that already at a young age, Psip1 cKO mice show motor deficits. In cerebellar neurons, LEDGF depletion results in more and smaller MeCP2 condensates. Bulk and comparative RNA sequencing of cerebellar extracts revealed downregulation of genes involved in synaptic transmission. Moreover, transcription factor network analysis showed that the differentially expressed genes are mainly regulated by the Polycomb repressive complex 2 (PRC2). Since the LEDGF/p75 binding partner MLL1 is part of the Trithorax Complex, the counterpart of PRC2 in gene regulation, our data highlight the importance of LEDGF/p75-mediated regulation of synaptic gene expression in the cerebellum through Trithorax.