Biology subjects

Viragova, S.

Publications and source records attributed to Viragova, S..

4 recordsLinked to original sources

bioRxiv2025

IL-25-induced memory ILC2s mediate long-term small intestinal adaptation

The adaptation of intestinal helminths to vertebrates evolved strategies to attenuate host tissue damage to support reproductive needs of parasites necessary to disseminate offspring to the environment. Helminths initiate the IL-25-mediated tuft cell-ILC2 circuit that enhances barrier protection of the host although viable parasites can target and limit the pathway. We used IL-25 to create small intestinal adaptation marked by anatomic, cell compositional and immunologic changes that persisted months after induction. Small intestinal adaptation was associated with heightened resistance to barrier pathogens, including in the lung, and sustained by transcriptionally and epigenetically modified, tissue-resident, memory-effector ILC2s distinct from those described by innate training; epithelial stem cells remained unaltered. Despite requiring IL-25 for induction, memory ILC2s maintained an activated state in the absence of multiple alarmins and supported mucosal resilience while avoiding adverse sensitization to chronic inflammation, revealing a pathway for deploying innate immune cells to coordinate a distributed mucosal defense.

immunology↗

bioRxiv2024

MAGIC matrices: freeform bioprinting materials to support complex and reproducible organoid morphogenesis

Complex and robust self-organization requires defined initial conditions and dynamic boundaries - neighboring tissues and extracellular matrix (ECM) that actively evolve to guide morphogenesis. A major challenge in tissue engineering is identifying material properties that mimic dynamic tissue boundaries but that are compatible with the engineering tools necessary for controlling the initial conditions of culture. Here we describe a highly tunable granular biomaterial, MAGIC matrix, that supports long-term bioprinting and gold-standard tissue self-organization. MAGIC matrix is designed for two temperature regimes: at 4 {degrees}C it exhibits reversible yield-stress behavior to support hours-long high-fidelity 3D printing without compromising cell viability; when transferred to cell culture at 37 {degrees}C, the material cross-links and exhibits viscoelasticity and stress relaxation that can be tuned to match numerous conditions, including that of reconstituted basement membrane matrices like Matrigel. We demonstrate that the timescale of stress relaxation and loss tangent are decoupled in MAGIC matrices, allowing us to test the role of stress relaxation rate and strain-dependence across formulations with identical storage and loss moduli. We find that fast absolute stress relaxation rates and large relative deformation magnitudes are required to optimize for morphogenesis. We apply optimized MAGIC matrices toward precise extrusion bioprinting of saturated cell suspensions directly into 3D culture. The ability to carefully control initial conditions for tissue growth yields dramatic increases in organoid reproducibility and complexity across multiple tissue types. We also fabricate perfusable 3D microphysiological systems that experience large strains in response to pressurization due to the compliant and dynamic tissue boundaries. Combined, our results both identify key parameters for optimal organoid morphogenesis in an engineered material and lay the foundation for fabricating more complex and reproducible tissue morphologies by canalizing their self-organization in both space and time.

bioengineering↗

bioRxiv2023

Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains

A key aspect of nutrient absorption is the exquisite division of labor across the length of the small intestine, with individual classes of micronutrients taken up at different positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum, and ileum. By examining fine-scale longitudinal segmentation of the mouse and human small intestines, we identified transcriptional signatures and upstream regulatory factors that define five domains of nutrient absorption, distinct from the three traditional sections. Spatially restricted expression programs were most prominent in nutrient-absorbing enterocytes but initially arose in intestinal stem cells residing in three regional populations. While a core signature was maintained across mice and humans with different diets and environments, domain properties were influenced by dietary changes. We established the functions of Ppar- and Cdx1 in patterning lipid metabolism in distal domains and generated a predictive model of additional transcription factors that direct domain identity. Molecular domain identity can be detected with machine learning, representing the first systematic method to computationally identify specific intestinal regions in mice. These findings provide a foundational framework for the identity and control of longitudinal zonation of absorption along the proximal:distal small intestinal axis.

genomics↗

bioRxiv2022

Phenotypic dissection of epithelial lineages and therapeutic manipulation of differentiation programs in human Adenoid Cystic Carcinomas

Adenoid Cystic Carcinoma (ACC) is a rare and aggressive form of salivary gland cancer, characterized by the co-existence within tumor tissues of two distinct populations of malignant cells, phenotypically similar to the myoepithelial and ductal lineages of normal salivary glands. Using a novel computational approach for single-cell RNA-seq analysis, we identified two cell-surface markers (CD49f, KIT) that enable the differential purification of myoepithelial-like (CD49fhigh/KITneg) and ductal-like (CD49flow/KIT+) cells from ACC patient derived xenografts (PDX). Using prospective xeno-transplantation experiments, we demonstrate that myoepithelial-like cells act as progenitors of ductal-like cells. Using three-dimensional (3D) organoid cultures, we demonstrate that agonists of retinoic acid (RA) signaling promote differentiation of myoepithelial-like cells into ductal-like cells, while inhibitors of RA signaling selectively kill ductal-like cells. Finally, we demonstrate that BMS493, an inverse agonist of RA signaling, can be successfully leveraged for the in vivo treatment of human ACCs.

cancer biology↗