Functions of Diverse Fibroblast Populations in Lung Health and Disease
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Dean Sheppard, MD
Professor of Medicine
University of California, San Francisco
Dean Sheppard is a Professor of Medicine. His research focuses on the molecular mechanisms underlying pulmonary (and other organ) fibrosis, acute lung injury and immune responses to solid tumors. One aim of the research is to identify new therapeutic targets to ultimately improve the treatment of each of these common diseases. The work began with basic investigation of how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues and how these responses contribute to the development of common lung diseases. Utilizing mice with global or conditional knockouts of the epithelial-restricted integrin, avß6, and the widely expressed integrins, a5ß1, a9ß1, avß5 and avß8, the lab has identified important roles for these integrins in models of each common lung disease and key steps upstream and downstream of the integrins that provide potential therapeutic targets. His lab identified the unique roles that 3 integrins, avß1, avß6 and avß8 play in activation of the growth factor, latent transforming growth factor beta (TGFß) and has identified critical roles for this process in acute lung injury, pulmonary fibrosis, post-natal brain development, and immunosuppression in the setting of cancer. Current work is using single cell RNA sequencing to understand the heterogeneity of cells that contribute to tissue fibrosis and using these results to generate novel murine lines to establish the lineage, fate and functional importance of each of the new cell states identified. The lab is also collaborating with Wendell Lim to use these data to engineer cells that delivery genetically encoded therapeutics at sites of fibrosis and acute lung injury and to improve cell-based therapies for solid tumors.
Summary
Dr. Sheppard will describe the diversity of fibroblasts in normal lungs and how molecularly defined subsets are located at distinct anatomical locations. In response to alveolar injury, resting alveolar fibroblasts give rise to several novel molecular subsets, including inflammatory, stress activated, fibrotic and proliferating fibroblasts. Deletion of resting alveolar fibroblasts increases the susceptibility of mice to acute lung injury, which is mediated by exaggerated expansion of gamma delta T cells that produce IL-17. Fibrotic fibroblasts, that are only present in fibrotic murine and human lungs, play an important role in driving pathologic fibrosis, but also play an important homeostatic role in preventing exaggerated lung inflammation. After induction these cells undergo clonal expansion that itself contributes to lung fibrosis in two different models. Injured alveolar epithelial cells are important inducers of fibrotic fibroblasts. One critical driver of the pro-fibrotic response of injured epithelial cells requires activation of the IRE1a limb of the unfolded protein response. We used a suite or IRE1a modulators to show that IRE1a in alveolar epithelial cells does not contribute to fibrosis through its canonical role in processing the stress-activated transcription factor, XBP-1, but rather acts through ribonuclease cleavage of other ER targeted RNÅs through a process called RIDD.
Learning Objectives:
1. Understand the molecular diversity of fibroblasts in normal lungs
2. Appreciate how novel molecular states emerge from resting lung fibroblasts in response to injury and how these states modulate inflammatory and fibrotic responses.
This page was last updated on Friday, March 6, 2026