Biology subjects

Kessler, J. A.

Publications and source records attributed to Kessler, J. A..

5 recordsLinked to original sources

bioRxiv2025

Differential Regulation of APOE4-Mediated Astrocytic Lipid Metabolism by BMP Signaling Exacerbates Alzheimers Disease Pathologies in Neurons

The two greatest risk factors for Alzheimers Disease (AD) are aging and Apolipoprotein E4 (APOE4) polymorphism, yet how these factors interact remain unclear. In this study, we investigate how bone morphogenetic protein (BMP) signaling, which increases with age, contributes to APOE4-induced lipid metabolic dysfunctions using induced-pluripotent stem cell (iPSC)-derived astrocytes and cocultured neurons. Surprisingly, BMP signaling differentially altered lipid droplet formation, cholesterol synthesis and breakdown, and fatty acid-oxidation in APOE4 compared to APOE3 astrocytes, and increased secretion of oxidized LDL (oxLDL). Furthermore, neurons cocultured with BMP4-treated APOE4 astrocytes showed altered transcriptomic profiles based on scRNA-seq as well as increased tau phosphorylation (p-tau). oxLDL treatment similarly increased p-tau and reduced neuronal survival. Conversely, lipid uptake inhibition in neurons rescued the BMP4/APOE4 astrocyte-induced neuronal phenotype. These data demonstrate key interactions between APOE4 and aging-associated molecular signaling in AD pathogenesis and establish a causal linkage between astrocytic lipid metabolism and neuronal tau hyperphosphorylation.

neuroscience↗

bioRxiv2025

Identification of Human Pluripotent Stem Cell Derived Astrocytic Progenitors that Correlate with Glioblastoma Subtypes

Recent studies have identified stem/progenitor cells in Glioblastoma multiforme (GBM) tumors that recapitulate developmental glial lineages in tumor progression, but whether non-malignant developmental glial progenitors share molecular characteristics with GBM tumor subtypes has not been extensively investigated. Here we present an approach that uses human pluripotent stem cells (hPSCs)-derived neural progenitors to study the developmental diversity of cells in the astrocytic lineage and how it correlates with GBM subtypes. Using a combination of single cell RNA sequencing of gliogenic stage neural progenitors and bulk RNA sequencing of cells that express combinations of GBM-associated cell surface markers, we identified two astrocytic progenitor populations that share gene expression profiles with the mesenchymal and proneural GBM subtypes respectively. Differential gene expression and pathway analyses of mesenchymal and proneural-associated progenitor clusters revealed enrichment in TGF-{beta} signaling and neuronal differentiation pathways respectively. These findings suggest that hPSC-derived astrocytic progenitors retain similar molecular heterogeneity as that observed in human fetal brain and GBM tumor cells. Identification of specific astrocyte progenitors that exhibit distinct GBM subtype transcriptomic profiles should facilitate development of therapies that target specific GBM cell populations. Significance StatementSignaling pathways that create heterogeneity during development are essential for the generation of functionally distinct cell types that coordinate to achieve the complexity of the nervous system. However, studies have demonstrated that molecular dysfunction in stem/progenitor cells that give rise to the diverse cell types during normal development may contribute to malignant outcomes, including brain tumors such as glioblastoma. Using human pluripotent stem cell (hPSC) as a model, we found that developmental signals that promote the generation of astrocytes also give rise to astrocyte progenitor cells that share molecular similarities with different brain tumor subtypes. The study provides a novel hPSC differentiation protocol for generating molecularly distinct populations of astrocyte progenitors, which may be utilized in disease modeling or drug testing for specific brain tumor subtypes.

developmental biology↗

bioRxiv2023

YAP and TAZ differentially regulate postnatal cortical progenitor proliferation and astrocyte differentiation

WW domain-containing transcription regulator 1 (TAZ) and Yes-associated protein (YAP) are transcriptional co-activators traditionally studied together as a part of the Hippo pathway and best known for their roles in stem cell proliferation and differentiation. Despite their similarities, TAZ and YAP can exert divergent cellular effects by differentially interacting with other signaling pathways that regulate stem cell maintenance or differentiation. In the developing central nervous system, In this study, we show that TAZ regulates astrocytic differentiation and maturation of postnatal neural stem and progenitor cells (NPCs), and that TAZ mediates some but not all of the effects of bone morphogenetic protein (BMP) signaling on astrocytic development. By contrast, TAZ and YAP both mediate effects on NPC fate of {beta}1-integrin and integrin-linked kinase (ILK) signaling, and these effects are dependent on extracellular matrix (ECM) cues. These findings demonstrate that TAZ and YAP perform divergent functions in the regulation of astrocyte differentiation, where YAP regulates cell cycle states of astrocytic progenitors and TAZ regulates differentiation and maturation from astrocytic progenitors into astrocytes. Summary StatementAstrocytes are accounts for nearly half of the cells in the central nervous system, where they perform a diverse array of physiological functions. During development, astrocytes are primarily generated after neuronal differentiation in a stepwise manner from multiple glial committed progenitor subtypes. How gliogenic progenitors maintain proliferative properties versus differentiate into astrocytes is not fully understood. This work aims to elucidate how environmental signals utilizes molecularly similar intracellular components to achieve distinct developmental outcomes. In addition, many of the cell types that are involved in glial development are also present in brain tumors including glioblastoma. Knowledge on mechanisms regulating proliferation and differentiation of glial progenitors will provide insights into differences and similarities between normal and malignant cells.

neuroscience↗

bioRxiv2022

Death induced by survival gene elimination (DISE) contributes to neurotoxicity in Alzheimer's disease

Alzheimers disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a cell death mechanism mediated by short (s) RNAs acting through the RNA induced silencing complex (RISC). DISE is thus a form of RNA interference, in which G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich 6mer seed matches in genes essential for cell survival, resulting in the activation of cell death pathways. Here, using Argonaute precipitation and RNAseq (Ago-RP-Seq), we analyze RISC-bound sRNAs to quantify 6mer seed toxicity in several model systems. In mouse AD models and aging brain, in induced pluripotent stem cell-derived neurons from AD patients, and in cells exposed to A{beta}42 oligomers, RISC-bound sRNAs show a shift to more toxic 6mer seeds compared to controls. In contrast, in brains of "SuperAgers", humans over age 80 who have superior memory performance, RISC-bound sRNAs are shifted to more nontoxic 6mer seeds. Cells depleted of nontoxic sRNAs are sensitized to A{beta}42-induced cell death, and reintroducing nontoxic RNAs is protective. Altogether, the correlation between DISE and A{beta}42 toxicity suggests that increasing the levels of nontoxic miRNAs in the brain or blocking the activity of toxic RISC-bound sRNAs could ameliorate neurodegeneration.

neuroscience↗

bioRxiv2018

A Combined Numerical and Experimental Investigation of Localized Electroporation-based Transfection and Sampling

Localized electroporation has evolved as an effective technology for the delivery of foreign molecules into adherent cells, and more recently, for the sampling of cytosolic content from a small population of cells. Unlike bulk electroporation, where the electric field is poorly controlled, localized electroporation benefits from the spatial localization of the electric field on a small areal fraction of the cell membrane, resulting in efficient molecular transport and high cell-viability. Although there have been numerous experimental reports, a mechanistic understanding of the different parameters involved in localized electroporation is lacking. In this work, we developed a multiphysics model that a) predicts the electro-pore distribution in response to the local transmembrane potential and b) calculates the molecular transport into and out of the cell based on the predicted pore-sizes. Using the model, we identify that cell membrane tension plays a crucial role in enhancing both the amount and the uniformity of molecular transport, particularly for large proteins and plasmids. We qualitatively validate the model predictions by delivering large molecules (fluorescent-tagged bovine serum albumin and mCherry encoding plasmid) and by sampling an exogeneous protein (tdTomato) in an engineered cell line. The findings presented here should inform the future design of microfluidic devices for localized electroporation based sampling, eventually paving the way for temporal, single-cell analysis.

biophysics↗