Biology subjects

Lowry, W. E.

Publications and source records attributed to Lowry, W. E..

6 recordsLinked to original sources

bioRxiv2026

Glutamine addiction is a therapeutic target to block emergency myelopoiesis

Inflammation-driven emergency myelopoiesis (EM) contributes to the progression of many solid cancers and inflammatory diseases, yet therapeutic strategies to selectively suppress EM without compromising hematopoiesis remain lacking. Here, we use functional and single-cell transcriptomic analyses to determine metabolic programs organizing the hematopoietic hierarchy, myeloid lineage commitment, and myeloid differentiation. We identify de novo glutamine biosynthesis as a stem cell-specific survival mechanism allowing independence from exogenous glutamine. We show that myeloid differentiation is characterized by Myc-driven upregulation of mitochondrial respiration, which is hyperactivated during EM and renders myeloid progenitors dependent on glutaminolysis to fuel the TCA cycle. Both genetic and pharmacologic targeting of glutaminase suppresses EM and impairs breast tumor progression by reducing intratumoral neutrophil infiltration. Our study defines a central role for Myc-glutaminolysis in driving EM, identifies glutaminolysis as a therapeutic target to normalize maladaptive EM, and highlights myeloid overproduction as a systemic problem requiring HSPC targeting. HIGHLIGHTSO_LIHSC survival depends on de novo glutamine biosynthesis via glutamine synthetase C_LIO_LIMyc hyperactivation drives mitochondrial biogenesis during emergency myelopoiesis C_LIO_LIMyeloid progenitors become glutamine-addicted to fuel Myc-driven TCA cycle activity C_LIO_LIGlutaminase deficiency in HSPCs blunts tumor-promoting neutrophil production C_LI ETOC BLURBOlson et al. show that emergency myelopoiesis, the inflammatory overproduction of myeloid cells that drives regeneration, depends on Myc-driven mitochondrial respiration and glutamine addiction in hematopoietic progenitors. Targeting glutaminase in hematopoietic stem and progenitor cells suppresses pathological myelopoiesis, reduces tumor-promoting neutrophil production, and slows breast tumor growth.

immunology↗

bioRxiv2020

Single-soma transcriptomics of tangle-bearing neurons in Alzheimer's disease reveals the signatures of tau-associated synaptic dysfunction

Aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is closely associated with neuronal death and cognitive decline in Alzheimers disease (AD). To define the signatures that distinguish between aggregation-prone and resistant cell states in AD, we developed a FACS-based method for the high-throughput isolation and transcriptome profiling of individual cells with cytoplasmic aggregates and profiled 63,110 somas from human AD brains. By comparing NFT-bearing and NFT-free somas within and across neuronal subtypes, we identified the cell-type-specific and shared states. NFT-bearing neurons shared a marked upregulation of genes associated with synaptic transmission, including a core set of 63 genes enriched for synaptic vesicle cycle and transsynaptic signaling, whereas glucose metabolism and oxidative phosphorylation changes were highly neuronal-subtype-specific. Apoptosis was modestly enriched in NFT-bearing neurons despite the strong link between tau and cell death. Our datasets provide a resource for investigating tau-mediated neurodegeneration and a platform for biomarker and drug target discovery.

neuroscience↗

bioRxiv2019

Identification of neural oscillations and epileptiform changes in human brain organoids

Brain organoids represent a powerful tool for the study of human neurological diseases, particularly those impacting brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes. This raises the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network behaviors reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from MECP2 mutant patients compared to isogenic controls accompanied by modest transcriptomic differences revealed by single cell analyses. We also rescue key physiological activities with an unconventional neuromodulatory drug, Pifithrin-. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

neuroscience↗

bioRxiv2018

A single cell transcriptomic analysis of human neocortical development

Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We defined single cell transcriptomic profiles for 40,000 cells at mid-gestation to identify cell types in the developing human neocortex. We define expression profiles corresponding to all known major cell types at this developmental period and identify multiple transcription factors and co-factors expressed in specific cell types, providing an unprecedented resource for understanding human neocortical development including the first single-cell characterization of human subplate neurons. We characterize major developmental trajectories during early neurogenesis, showing that cell type differentiation occurs on a continuum that involves transitions that tie cell cycle progression with early cell fate decisions. We use these data to deconvolute regulatory networks and map neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.\n\nOne Sentence SummaryComprehensive single cell transcriptomes in developing human cortex inform models of cell diversity, differentiation and disease risk.

neuroscience↗

bioRxiv2017

TDG Regulates Cell Cycle Progression In Human Neural Progenitors

As cells divide, they must replicate both their DNA and generate a new set of histone proteins. The newly synthesized daughter strands and histones are unmodified and must therefore be covalently modified to allow for transmission of important epigenetic marks to daughter cells. Human pluripotent stem cells (hPSCs) display a unique cell cycle profile, and control of the cell cycle is known to be critical for their proper differentiation and survival. A major unresolved question is how hPSCs regulate their DNA methylation status through the cell cycle, namely how passive and active demethylation work to maintain a stable genome. TDG, an embryonic essential gene, has been recently implicated as a major enzyme involved in demethylation1. Here we present new data showing that TDG regulates cell cycle related gene expression in human neural progenitors (NPCs) derived from hPSCs and controls their capacity for neural differentiation. These observations suggest that TDG and active demethylation play an important role in hPSC cell cycle regulation and differentiation.

molecular biology↗

bioRxiv2017

Loss of MECP2 leads to telomere dysfunction and neuronal stress

To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression changes including induction of a Senescence Associated Secretory Phenotype (SASP) program. Patient derived Neurons made without MECP2 show signs of stress, including induction of p53, and senescence. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. These disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to an increase in aspects of neuronal aging.

developmental biology↗