Fibroblasts—cells that build and repair tissue—are being controlled by a specific type of immune cell, the type-2 lymphocyte, in ways that could either heal organs or scar them for life. This matters because fibrosis—the progressive stiffening and scarring of organs like the lungs and pancreas—is a major global health problem with few effective treatments. Current therapies fail partly because scientists do not understand how immune cells and fibroblasts talk to each other in different tissues and at different stages of disease. The researchers have already discovered that type-2 lymphocytes sit next to fibroblast-progenitor cells in solid organs, forming specialised niches. They now want to map these conversations cell by cell. If successful, this work could reveal new drug targets for stopping fibrosis while preserving the normal healing that fibroblasts perform. It might also improve recovery from acute injuries like pancreatitis or viral lung infections. The project is fundamental science—it asks how a basic tissue-repair system works—but a clearer picture of these immune-fibroblast interactions could eventually shift how doctors treat chronic scarring diseases that currently have no cure.
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Fibroblasts are critical for organ homeostasis and tissue-repair, but also contribute to fibrosis in serious diseases. Immune cells regulate fibroblast function, although the complex tissue- temporal- and disease-specific features of such interactions have made therapeutic targeting difficult. We found that tissue-resident type-2 lymphocytes control novel fibroblast-progenitor niches in solid organs. Hence, we hypothesize that type-2 lymphocytes orchestrate local fibroblast homeostasis and guide their biology throughout tissue- regeneration, while perturbations of this axis underpin fibrosis. Using cutting-edge single-cell and spatial techniques we will reveal the cellular and molecular makeup of specific immune-fibroblast niches in organs, and importantly, discover how these different cells interact dynamically. We will then use advanced 3D cell-cultures that model the complex organ environment, and refined mouse models of both tissue-repair and tissue-fibrosis to determine how specific lymphocytes locally control fibroblast function. We will simultaneously define this novel immune-fibroblast progenitor niche in human organs using highly-multiplexed spatial and single-cell approaches; conserved mechanisms will be identified and developed as therapeutic targets. We will focus on the pancreas and lung, where a better understanding of tissue-regeneration post injury (i.e. acute pancreatitis, viral infection, allergens or toxins) or mechanisms of fibrosis (i.e. chronic pancreatitis, lung fibrosis) will address major global health challenges.
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