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Hester, M. E.

Publications and source records attributed to Hester, M. E..

2 recordsLinked to original sources
bioRxiv2021

Patient-Derived Organoids Recapitulate Intrinsic Immune Landscapes and Progenitor Populations of Glioblastoma.

Glioblastoma stem cells (GSCs) are highly self-renewing, resistant to therapy, and are able to form lethal tumors1, 2. Tumor organoids have been developed to study tumor evolution1-4, and while GSCs can form organoids for glioblastoma multiforme, our understanding of their intrinsic immune, metabolic, genetic, and molecular programs is limited. To address this, we deeply characterized GSC-derived GBM organoids using a modified protocol (GBMOsm) from several patient-derived GSCs and found they develop into complex 3D tissues with unique self-organization, cancerous metabolic states, and burdensome genetic landscapes. We discovered that GBMOsc recapitulate the presence of two important cell populations thought to drive GBM progression, SATB2+ and HOPX+ progenitors. Despite being devoid of immune cells, transcriptomic analysis across GBMOsc revealed an immune-like molecular program, enriched in cytokine, antigen presentation and processing, T-cell receptor inhibitors, and interferon genes. We determined that SATB2+ and HOPX+ populations contribute to this immune and interferon landscape in GBM in vivo and GBMOsm. Our work deepens our understanding of the intrinsic molecular and cellular architecture of GSC-derived GBMO and defines a novel GBMOsc intrinsic immune-like program.

neuroscience↗
bioRxiv2021

Spatially resolved transcriptomics reveals unique gene signatures associated with human temporal cortical architecture and Alzheimer's pathology

Alzheimers disease (AD) is pathologically characterized by amyloid beta (A{beta}) plaques, neurofibrillary tangles (tau aggregates), and alterations in microglia, astrocytes and oligodendrocytes. The mesial temporal lobe is a vulnerable brain region in early AD; however, little is known about the transcriptome-scale gene expression in this region and its relation to AD pathology. Here we use the 10x Genomics Visium platform in combination with co-immunofluorescence staining of AD-associated pathological markers to define the spatial topography of gene expression in the middle temporal gyrus (MTG) from both early AD and age- and gender-matched control cases. We identify unique marker genes for six cortical layers and the adjacent white matter as well as gene expression patterns and alterations that showcase unique gene signatures and pathways associated with a range of AD pathology. Also, gene co-expression analyses of differentially expressed genes (DEGs) between AD and controls reveal four unique gene modules, which significantly change their co-expression patterns in the presence of variations of AD pathology. Furthermore, we validate the changes of key representative DEGs that are associated with AD pathology in neurons, microglia, astrocytes and oligodendrocytes using single-molecule fluorescent in situ hybridization. In summary, we provide a rich resource for the spatial transcriptomic profile of the human MTG, which will contribute to our understanding of the complex architecture and AD pathology of this vulnerable brain region.

neuroscience↗