THE CONSULT: Professor Paul Klenerman talks with Professor Christopher Buckley about his recent papers.
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In this episode of 'The Consult,' Professor Paul Klenerman interviews Professor Christopher Buckley about his groundbreaking research on fibroblasts and their evolving role in immune-mediated inflammatory diseases. Buckley traces his journey from biochemistry to rheumatology, highlighting how fibroblasts—once seen merely as structural cells—have emerged as central players in tissue inflammation, fibrosis, and immune regulation. The discussion centers on two key papers: one in JCI Insight on systemic sclerosis, which revealed functional and spatial differences between migratory and resident fibroblasts, and another in Nature Communications on Sjögren’s syndrome, where a novel 'immunopericyte' was identified as a key driver of tertiary lymphoid structures. These findings underscore the importance of cellular location, embryonic origin, and tissue-specific microenvironments in shaping cell function. The conversation also explores therapeutic frontiers, including the potential of CAR T-cell therapy and morphogen-based reprogramming to target pathogenic fibroblast subsets. Buckley envisions a future where medicine shifts from anatomical to cellular taxonomy, using single-cell and spatial transcriptomics to move from correlative to causal understanding of disease.
Fibroblasts are not passive structural cells but active regulators of immune responses and tissue homeostasis, with distinct functional roles based on location.
Spatial transcriptomics and single-cell sequencing reveal that fibroblast heterogeneity is driven by embryonic origin and microenvironmental cues, not just gene expression.
The discovery of 'immunopericytes' in Sjögren’s syndrome explains the formation of pathogenic tertiary lymphoid structures, offering new therapeutic targets.
Therapeutic strategies like CAR T-cells or morphogen-based reprogramming may one day allow selective targeting of pathogenic fibroblast subsets.
The future of medicine lies in a cellular taxonomy—moving beyond organ-based classification to a system based on cell identity and function across tissues.
Introduction and Background
Paul Klenerman welcomes Christopher Buckley and begins with a brief overview of his academic journey from biochemistry to rheumatology, setting the stage for the discussion on fibroblasts.
The Evolution of Fibroblast Research
Buckley explains how fibroblasts were historically dismissed as mere structural cells, and how the rise of stromal immunology and single-cell technologies revealed their active role in immune regulation and tissue inflammation.
Fibroblast Heterogeneity in Systemic Sclerosis
“The fibroblasts that grow out fast are not keeping company with the endothelium. They're the leukocyte-rich ones. Want to do that kind of function.”
Spatial Transcriptomics and Cellular Identity
“Location dictates function, doesn't it? So, I think you need the two components. What's the cell census? The total number of cells are there different flavors and then where are they located?”
Embryonic Patterning and Disease Specificity
“The different joints that you need to use to write are different to the ones you have to claw. And you see this in the gut, of course. The large bowel is fundamentally different to the small bowel.”
“Mice lie, monkeys exaggerate, humans tell the truth. And the tissue is where the issue is.”
“If the preliminary data from the CD19 CAR T-cell data, in some diseases like lupus, single shot of that has lasted, people have not needed another therapy for three or four years. So that's the ultimate cure.”
“Location dictates function, doesn't it? So, I think you need the two components. What's the cell census? The total number of cells are there different flavors and then where are they located?”
Host
Guest
Christopher Buckley
person
Paul Klenerman
person
Systemic Sclerosis
other
Sjögren’s Syndrome
other
CD19 CAR T-cell
other
Francesca Barone
person
Burkhard Ludwig
person
Mike Brenner
person
JCI Insight
other
Nature Communications
other
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