Novel organoid models to resolve fibroblast-epithelial-ECM niche regulation

The National Institute of General Medical Sciences awarded The University of Iowa $427,625 on August 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop novel organoid models that resolve fibroblast-epithelial-extracellular matrix niche regulation.

The funded research addresses how fibroblasts signal with and sense their environment, with particular focus on fibroblast-epithelial cell communication and interaction with the extracellular matrix. The investigator will develop reductionist organoid systems that co-culture epithelial cells and fibroblasts in three-dimensional environments with precise manipulation of extracellular matrix composition and mechanics. These models will capture cellular heterogeneity, paracrine signaling, and matrix remodeling absent in conventional systems. The work will identify ligand-receptor signaling pathways between fibroblasts and basal epithelial cells, test how alterations to fibroblast identity disrupt this communication, determine whether fibroblasts produce extracellular matrix proteins to support basal epithelial cells, and investigate how extracellular matrix mechanics and composition shape fibroblast-epithelial crosstalk. The research will integrate these findings with genetically engineered mouse models to dissect specific signaling pathways. Understanding these mechanisms addresses disruption of fibroblast-epithelial-extracellular matrix communication, a hallmark of chronic diseases including fibrosis and cancer.

Performance occurs in Iowa City, Iowa, with a period of performance from August 1, 2026, through May 31, 2031. The award is structured as a Project Grant, the standard assistance type for investigator-initiated research under this program.

Abstract

The central question we aim to address in this proposal is how fibroblasts signal with and sense their environment. Fibroblasts are mesenchymal cells that construct, remodel, and sense the extracellular matrix (ECM) and communicate with neighboring epithelial cells, shaping tissue repair and disease. Disruption of fibroblast-epithelial-ECM communication is a hallmark of chronic diseases such as fibrosis and cancer. Despite this importance, the mechanistic principles that govern fibroblast signaling remain poorly understood. My laboratory develops reductionist organoid systems to model these interactions in a controlled manner. We CO- culture epithelial cells and fibroblasts in 3D systems that allow precise manipulation of the ECM. These models capture cellular heterogeneity, paracrine signaling, and matrix remodeling that are absent in conventional systems. We combine these models with genetically engineered mice to dissect specific signaling pathways. Two primary questions guide this proposal: (1) how do fibroblasts signal to and interact with their neighboring epithelial cells? (2) how do fibroblasts and epithelial cells interact with, and respond to, the ECM? To address question 1, we will identify ligand-receptor signaling pathways between fibroblasts and basal epithelial cells. We will test how altering fibroblast identity disrupts communication with the basal epithelium. We will then determine whether fibroblasts produce ECM proteins to physically support basal epithelial cells in organoids. To address question 2, we will investigate how ECM mechanics and composition shape fibroblast-epithelial crosstalk and function. We will stiffen basement membrane matrices in a controlled, tunable manner and assess the fibroblast-epithelial cell niche across a range of physiological and pathological stiffnesses. Our research integrates cell biology, matrix biology, mechanobiology, and regenerative medicine. Collectively, these directions provide a unique opportunity to merge cell-cell communication with mechanobiology to examine how fibroblasts interact with their environment. By uncovering conserved molecular principles of cell communication, this work will advance our understanding of how cell-cell and cell-matrix signaling drive disease pathogenesis such as cancer and fibrosis.