Nielsen, O. H. | bioRxiv Science

bioRxiv2024

JAK/STAT signaling promotes the emergence of unique cell states in ulcerative colitis

The intestinal epithelium forms a barrier to the lumen and ensures uptake of vital nutrients. During inflammatory diseases, such as ulcerative colitis (UC), this barrier is compromised. Here, we perform single-cell RNA sequencing (scRNA-seq) of epithelial cells and outline patterns of cell fate decisions in healthy individuals and patients with UC. We demonstrate that lineage biased progenitors are major sources of normal tissue replenishment, and that patterns of cell behavior are profoundly altered in UC. We furthermore identify unique regenerative cell states linked to JAK/STAT activation extending into the non-inflamed areas of the colon. In organoid models, this can be mimicked by cytokine mediated activation of JAK/STAT leading to the emergence of cell populations with regenerative potential. These findings have profound implications for our understanding of tissue regeneration and illustrates how cytokine signaling influences cell fate decisions. This suggests widespread consequences in patients with chronic ulcerative conditions.

cell biology↗

bioRxiv2021

Single-cell characterisation of mononuclear phagocytes in the human intestinal mucosa

Mononuclear phagocytes (MNP), including macrophages and classical dendritic cells (cDC), are highly heterogeneous cells with distinct functions. Understanding MNP complexity in the intestinal lamina propria (LP), particularly in humans, has proved difficult due to the expression of overlapping phenotypic markers and the inability to isolate these cells without contamination from gut-associated lymphoid tissues (GALT). Here, we exploited our novel method for isolation of human GALT-free LP to carry out single-cell (sc)RNA-seq, CITE-seq and flow cytometry analysis of human ileal and colonic LP MNPs. As well as classical monocytes, non-classical monocytes, mature macrophage subsets, cDC1s, and cDC2s, we identified a CD1c+ cDC subset with features of both cDC2 and monocytes, which were transcriptionally similar to the recently described cDC3. While similar MNP subsets were present in both ileal and colonic LP, the proportions and transcriptional profiles of these populations differed between these sites and in diseased states, indicating local specialization and environmental imprinting. Using computational trajectory tools, we identified putative early committed pre-cDC subsets and developmental intermediates of mature cDC1, cDC2 and cDC3, as well as monocyte-to-macrophage trajectories. Collectively, our results provide novel insights into the heterogeneity and development of intestinal LP MNP and an important framework for studying the role of these populations in intestinal homeostasis and disease. One sentence summaryFenton and Wulff et al. use single-cell methods to explore the complexity of the mononuclear phagocyte compartment of the human intestinal lamina propria, identifying distinct dendritic cell and macrophage subsets, site-specific transcriptional signatures, and lineage-specific precursors.

immunology↗