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Hedgehog gradient in the stroma maintains niche diversity and organ function [Drop-seq]

ABSTRACT: A single-cell transcriptional analysis was performed on GLI2+ stromal cells from the adult murine lung. Whole adult murine lung tissue was dissociated to single cells and subjected to fluorescence activated cell sorting (FACS) to select all live GLI2+ cells. The single cell RNA-sequencing library was then subsequently generated. Cells were sequenced at a depth of ~60,000 reads/cell. We captured approximately 4,600 cells with a median of 2,246 genes detected per cell utilizing a droplet-based barcoding approach to capture single cells for RNA sequencing. The results demonstrate that the GLI2+ population is segregated into distinct stromal subtypes along the proximal-distal axis of the lung with distinct functional contribution to matrix production and paracrine signaling within their distinctive niche.

ORGANISM(S): Mus musculus

PROVIDER: GSE102591 | GEO | 2018/08/08

REPOSITORIES: GEO

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Project description:Stomach and intestinal epithelial cells are maintained by the activity of stem cells located in the isthmus and crypt, respectively1,2. Recent studies have demonstrated a surprisingly conserved role for Wnt signaling in stomach and intestinal development and stem cells3,4. Although accumulating evidence suggests that intestinal stromal cells secrete Wnt ligands to promote stem cell renewal5-10, the source of stomach Wnt ligands is still unclear. Moreover, how these gastrointestinal stem cell niche signals are produced is currently unknown. By performing single cell analysis of gastrointestinal stromal cells, we identified cell populations with transcriptome signatures that are conserved between the stomach and intestine. In close proximity to gastrointestinal epithelial cells, these cells highly expressed pericyte markers and Wnt ligands. They also were enriched for Hh signaling, which plays a key role in gut development11,12. A recent study has shown that intestinal pericryptal cells co-express Hh target and Wnt ligand genes8. To define their relationship, we analyzed mice with Hh gain of function in the pericyte-like stromal cells conserved between the stomach and intestine, and found increased levels of Wnt ligands, supporting Hh regulation of stromal Wnt ligand expression. Moreover, utilizing Sufu and Spop double knockout mice, which stabilized GLI2, a key Hh mediator in the gut, we were able to map GLI2 binding sites genome-wide and analyze super enhancers. This work demonstrates GLI2 activation of stromal Wnt ligands through enhancers that are conserved between the stomach and intestine. To determine the significance of Wnt secreting gastrointestinal stromal cells, we genetically inhibited Wnt secretion from the perictye-like or broad stromal cells, demonstrating their roles in gastrointestinal regeneration and development, respectively. Our work not only identifies the conserved gastrointestinal stromal niche cell populations but also reveals their underlying signaling and epigenetic mechanisms.

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Hedgehog gradient in the stroma maintains niche diversity and organ function [Drop-seq]

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