Biology subjects

Monell, A.

Publications and source records attributed to Monell, A..

4 recordsLinked to original sources

bioRxiv2024

Functional Diversity of Memory CD8 T Cells is Spatiotemporally Imprinted

Tissue-resident memory CD8 T cells (TRM) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) TRM cells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct TRM transcriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. TRM populations were spatially segregated: with more effector- and memory-like TRM preferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain TRM differentiation and functional diversity, including different TGF{beta} sources. Alterations in the cellular networks induced by loss of TGF{beta}RII expression revealed a model consistent with TGF{beta} promoting progressive TRM maturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.

immunology↗

bioRxiv2024

Re-activation of neurogenic niches in aging brain

Recent studies proposing induced glia-to-neuron conversion raised the potential for generating new neurons to replace those lost due to injury, aging or neurodegenerative diseases. Here, single-cell spatial transcriptomics [Multiplexed Error Robust Fluorescence In Situ Hybridization (MERFISH)] is used to construct a spatial cell atlas of the subventricular and dentate gyrus neurogenic niches of young and aged adult murine brain. RNAs that encode the RNA binding protein Polypyrimidine Tract-Binding Protein (PTBP1) in the aged murine brain are determined to be highest in glia that line previously active neurogenic niches. A glial cell population with ependymal character within an initially quiescent subventricular neurogenic niche in the aged murine brain is identified that upon transient suppression of PTBP1 reenters the cell cycle, replicates DNA, and converts into neurons through a canonical adult neurogenesis pathway. Glia-derived neurons migrate from this niche, with some neurons transiting to the striatum and acquiring a transcriptome characteristic of GABAergic inhibitory neurons. Similar PTBP1 expressing quiescent glia are identified in the corresponding neurogenic niche of aged human brain. Thus, transient reduction of PTBP1 holds potential for inducing the generation of new neurons in quiescent neurogenic niches of the aged nervous system, thereby offering promising therapeutic applications. Bullet point summary1) Single-cell spatial transcriptomics is used to validate active neurogenesis in the two neurogenic niches of the young adult murine brain, determine that those niches are quiescent in the aging adult brain of mice, and demonstrate the absence of neurogenesis in the aging human brain. 2) The RNA binding protein PTBP1 is determined to be most highly expressed within glia that line the aged murine and human neurogenic niches, with its transient reduction sufficient in mice to activate/re-activate expression of genes characteristic of immature neurons. 3) Suppression of PTBP1 using a single intra-cerebral-ventricular injection of PTBP1-targeting antisense oligonucleotide (ASO) induces generation of new immature neurons in the neurogenic niches of the aged mouse brain via a canonical adult neurogenesis pathway. 4) Single-cell RNA signature tracing is used to identify a) a subclass of ependymal cells in a previously quiescent neurogenic niche of the aged mouse brain that convert into GABAergic inhibitory neurons following transient suppression of PTBP1, and b) the molecular steps in the conversion process including cell cycle re-entry, DNA replication, and transcriptome changes that mimic canonical neurogenesis. 5) A similar class of PTBP1-expressing ependymal cells lining the ventricle of the aging non-human primate and human brains is identified, suggesting the promise of re-activation of neurogenesis as a therapeutic approach in humans.

neuroscience↗

bioRxiv2023

Time-resolved single-cell and spatial gene regulatory atlas of plants under pathogen attack

Plant leaf intercellular space provides a nutrient-rich and heterogeneous niche for microbes that critically impacts plant health. However, how individual plant cells respond to heterogeneous microbial colonization remains largely elusive. Here, by time-resolved simultaneous single-cell transcriptome and epigenome profiling of plants (Arabidopsis thaliana) infected by virulent and avirulent bacterial pathogens (Pseudomonas syringae), we present cell atlases with gene regulatory logic involving transcription factors, putative cis-regulatory elements, and target genes associated with disease and immunity. We also identify previously uncharacterized cell populations with distinct immune gene expression within major developmental cell types. Furthermore, we employ time-resolved spatial transcriptomics to reveal spatial heterogeneity of plant immune responses linked to pathogen distribution. Integrating our single-cell multiomics and spatial omics data enables spatiotemporal mapping of defense gene regulatory logic with pathogen cells. Our study provides a molecularly-defined spatiotemporal map of plant-microbe interaction at the single-cell resolution.

plant biology↗

bioRxiv2022

Bento: A toolkit for subcellular analysis of spatial transcriptomics data

The spatial organization of molecules in a cell is essential for performing their functions. Spatial transcriptomics technologies have opened the door to characterization of cellular and subcellular organization. While current computational methods focus on discerning tissue architecture, cell-cell interactions and spatial expression patterns, these approaches are limited to investigating spatial variation at the multicellular scale. We present Bento, a Python toolkit that fully takes advantage of single-molecule information to enable spatial analysis at the subcellular scale. Bento ingests molecular coordinates and segmentation boundaries to perform three fundamental analyses: defining subcellular domains, annotating localization patterns, and quantifying gene-gene colocalization. To demonstrate the toolkit, we apply these methods to a variety of datasets including U2-OS cells (MERFISH), 3T3 cells (seqFISH+), and treated cardiomyocytes (Molecular Cartography). We quantify RNA localization changes in cardiomyocytes identifying mRNA depletion of critical cardiac disease-associated genes RBM20 and CACNB2 from the endoplasmic reticulum upon doxorubicin treatment. The Bento package is a member of the open-source Scverse ecosystem, enabling integration with other single-cell omics analysis tools.

bioinformatics↗