RESUMEN
WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
RESUMEN
Astroblastoma, a rare glial tumor of the central nervous system, presents diagnostic and therapeutic challenges due to its low incidence and variable clinical presentations. In this case study, we present the case of an 11-year-old boy with high-grade astroblastoma, highlighting the complexities in diagnosis and treatment. The clinical presentation initially involved right-sided motor weakness, which, after undergoing a brain MRI, revealed a large solid cystic mass in the left parietal lobe. Histopathological examination after undergoing surgery confirmed an astroblastoma with high-grade features, characterized by increased cellularity and high mitotic activity. Immunostaining patterns supported the glial origin of the tumor. Gross total resection remains the primary approach for its treatment, but adjuvant therapies for high-grade astroblastomas are still evolving, offering potential life-changing possibilities for the future. Due to its rarity, collecting sufficient data to develop an effective treatment protocol for this uncommon tumor is very challenging. This case underscores the importance of combined efforts and ongoing research to effectively navigate the diagnosis and treatment of astroblastoma.