Biology subjects

Schrode, N.

Publications and source records attributed to Schrode, N..

6 recordsLinked to original sources

bioRxiv2026

A transcriptional continuum links viral burden and host-cell biology in human lymphoid tissue

Human immunodeficiency virus (HIV-1) persistence in lymphoid tissue remains a major barrier to cure, yet infected cells are commonly represented using discrete categories that may obscure biologically meaningful heterogeneity. Using an ex vivo human tonsil explant model and single-cell RNA sequencing of more than 42,000 T cells, we show that HIV transcription spans a structured continuum and that viral transcriptional burden functions as an organizing axis of host-cell biology. Across the continuum, increasing HIV transcription is associated with coordinated remodeling of immune, inflammatory, metabolic, and redox-associated programs. Lower transcriptional tiers were enriched for innate sensing and inflammasome-associated responses, whereas higher tiers exhibited activation of oxidative phosphorylation and redox-buffering pathways. Antiretroviral therapy preferentially depleted highly transcriptionally active populations while preserving lower and intermediate tiers, resulting in compression rather than elimination of the continuum. Together, these findings provide a quantitative framework for interpreting HIV transcriptional heterogeneity within human lymphoid tissue and suggest that persistent viral activity reflects a spectrum of host-virus states rather than a single infected-cell population. By linking viral transcriptional burden to distinct host-cell programs, this framework may inform future strategies to reduce HIV persistence and its associated inflammatory consequences.

immunology↗

bioRxiv2024

Mapping of Multilineage Tumor Cell Populations in Mouse Bladder Cancer

In bladder cancer (BLCA), the cellular expression of lineage markers with predictive biomarker function can have important implications for tumor progression, treatment response, and survival. However, tumor heterogeneity and the coexistence of distinct tumor subpopulations can complicate the utility of using a primary, clinically assigned tumor signature. In this report, we have applied the reference atlas, Tabula Sapiens, and deep learning model, UniCell, to conduct in-depth transcriptional analysis of unique lineage marker-defined cell clusters in a carcinogen (BBN) induced bladder cancer model. UniCell deconvolution has identified tumor populations, including urothelial, adenocarcinoma, squamous cell carcinoma, and mesenchymal tumor populations, each with cell-intrinsic gene expression signatures relevant to human BLCA progression. The identified tumor clusters contain uniquely basal, luminal, stromal, or hybrid cells in cell lineage marker expression. To understand the significance of these populations during progression, we used trajectory and pseudo-time analysis to show that cells uniquely basal are plastic in lineage identity and can evolve to form tumor populations composed of other lineage marker-defined signatures. Finally, pathway and drug enrichment analysis of tumor cell clusters were used to identify therapeutics that may preferentially target the identified tumor cell populations. These data collectively define a molecular template that may uniquely profile molecular plasticity occurring during progression and response to therapy with important implications for human disease. SignificanceTumor heterogeneity is a mechanism for treatment resistance. Our study defines unique tumor subpopulations having differential therapeutic sensitivities and potential for lineage plasticity. Our modeling may impact the treatment of BLCA patients.

cancer biology↗

bioRxiv2023

Generation and expansion of transitional lung organoids from human pluripotent stem cells

Human lungs contain unique cell populations in distal respiratory airways (RAs). These populations accumulate in patients with lung injury, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Their lineage potentials and roles are unknown, however. As they are absent in rodents, deeper understanding of these cells requires a human in vitro model. Here we report the generation from human pluripotent stem cells (hPSCs) of expandable spheres ( induced respiratory airway progenitors (iRAPs)) consisting of all RA-associated cell types. iRAPs could differentiate into type 1 (AT1) and type 2 alveolar (AT2) epithelial cells in defined conditions, showing that alveolar cells can be derived from RAs. iRAPs with deletion of HPS1, which causes pulmonary fibrosis in humans, display defects that are hallmarks of IPF, indicating involvement of intrinsic dysfunction of RA-associated cells in IPF. iRAPs thus provide a model to gain insight into human lung regeneration and into pathogenesis of IPF.

cell biology↗

bioRxiv2021

Understanding Mechanisms of Chamber-Specific Differentiation Through Combination of Lineage Tracing and Single Cell Transcriptomics

The specification and differentiation of atrial and ventricular myocardial cell types during development is incompletely understood. We have previously shown that Foxa2 expression during gastrulation identifies a population of ventricular fated progenitors, allowing for labeling of these cells prior to the morphogenetic events that lead to chamber formation and acquisition of bona fide atrial or ventricular identity. In this study, we performed single cell RNA sequencing of Foxa2Cre;mTmG embryos at the cardiac crescent (E8.25), primitive heart tube (E8.75) and heart tube (E9.25) stage in order to understand the transcriptional mechanisms underlying formation of atrial and ventricular cell types at the earliest stages of cardiac development. We find that progression towards differentiated myocardial cell types occurs primarily based on heart field progenitor identity, and that different progenitor populations contribute to ventricular or atrial identity through separate differentiation mechanisms. We identified a number of candidate markers that define such differentiation processes, as well as differential regulation of metabolic processes that distinguish atrial and ventricular fated cells at the earliest stages of development. We further show that exogenous injection with retinoic acid during formation of the cardiac primordia causes defects in ventricular chamber size and is associated with dysregulation in FGF signaling in anterior second heart field cells and a shunt in differentiation towards orthogonal lineages. Retinoic acid also causes defects in cell-cycle exit in myocardial committed progenitors that result in formation of hypomorphic ventricles with decreased expression of important metabolic processes and sarcomere assembly. Collectively, our data identify, at a single cell level, distinct lineage trajectories during cardiac progenitor cell specification and differentiation, and the precise effects of manipulating cardiac progenitor field patterning via exogenous retinoic acid signaling.

developmental biology↗

bioRxiv2020

Cell-type specific gene expression profiling in heterogeneous in vitro cultures using epitope-tagged RPL22

Genetic and genomic studies of brain disease increasingly demonstrate disease-associated interactions between the cell types of the brain. Increasingly complex and more physiologically relevant human induced pluripotent stem cell (hiPSC)-based models better explore the molecular mechanisms underlying disease, but also challenge our ability to resolve cell-type specific perturbations. Here we report an extension of the RiboTag system, first developed to achieve cell-type restricted expression of epitope-tagged ribosomal protein (RPL22) in mouse tissue, to a variety of in vitro applications, including immortalized cell lines, primary mouse astrocytes, and hiPSC-derived neurons. RiboTag expression enables efficient depletion of off-target RNA in mixed species primary co-cultures and in hiPSC-derived neural progenitor cells, motor neurons, and GABAergic neurons. Nonetheless, depletion efficiency varies across independent experimental replicates. The challenges and potential of implementing RiboTags in complex in vitro cultures are discussed.

molecular biology↗

bioRxiv2019

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimers Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H+-ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

neuroscience↗