Octavia Title: Vcam1 in endothelial and stromal cells regulates hematopoietic stem cell contact with the niche.
Alice Title: A Novel Model of Diffuse Midline Glioma in Zebrafish To Define Tumor Initation
Octavia Abstract: Hematopoietic stem and progenitor cells (HSPCs) are essential for differentiation into all blood cell types. In mammals, the interaction between HSPCs and the fetal liver niche during development is critical for stem cell maturation. Integrin alpha 4 (Itga4) on HSPCs and vascular cell adhesion molecule (Vcam1) on niche cells are critical for HSPC colonization of the fetal liver (FL). Itga4 and Vcam1 also function in the zebrafish equivalent of the FL, the caudal hematopoietic tissue (CHT), however, the specific niche cells that express Vcam1 remain unclear. Using multiple approaches, including fluorescent in situ hybridization, we found Vcam1 is expressed in endothelial cells (ECs) and mesenchymal stromal cells (MSCs), but not macrophages. Time-lapse live imaging of Itga4 mutants showed that the Itga4-Vcam1 axis is required for HSPC retention in the CHT niche. Our results show that Itga4 on HSPCs and Vcam1 on ECs and MSCs are involved in retention in the CHT niche.
Alice Abstract: Diffuse midline glioma (DMG), previously defined as diffuse intrinsic pontine glioma (DIPG), is a highly aggressive brain tumor that appears in children between 4-9 years of age and is always lethal within 1-2 years after diagnosis. These cancers are very rare, with only a few hundred children being diagnosed in the US each year. For decades, there has been no significant improvement in treatment options for DIPG/DMG, making it a high priority for further investigation. The development of new DIPG/DMG animal models is critical for advancing our understanding of this deadly brain cancer. To address this, we developed a zebrafish model of DMG/DIPG aimed at capturing the earliest stages of tumor development and dissecting mechanisms of tumor initiation in a vertebrate developmental context. We over-expressed DIPG/DMG oncogenes in zebrafish oligodendrocyte precursor cells (OPCs) using the myelin basic protein (mbp) promoter. Together with mbp:Cas9 and U6-driven gRNAs to generate spontaneous tumor suppressor mutations (ptena, ptenb, tp53), we observed aggressive and invasive lesions from 7-8 weeks, and lethality from 10-12 weeks. The mbp:GFP reporter allows direct observation of OPCs in the central nervous system (CNS). Using live imaging at early developmental stages, we identified a potential tumor initiation window at 8 days post-fertilization (dpf). To further investigate early cellular changes, we isolated GFP-positive cells at 8 and 14 dpf for single-cell RNA sequencing. This novel developmental model offers a unique platform to study early tumorigenesis in DMG and has the potential to uncover biomarkers and therapeutic targets for early intervention.
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