Defining the structure, signals, and cellular elements of the gastric mesenchymal niche

Manieri, Elisa; Tie, Guodong; Seruggia, Davide; Madha, Shariq; Maglieri, Adrianna; Huang, Kun; Fujiwara, Yuko; Zhang, Kevin; Orkin, Stuart H.; McCarthy, Neil; Shivdasani, Ramesh A.

doi:10.1101/2023.02.11.527728

Cited by 2 publications

(1 citation statement)

References 65 publications

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“…The second CBF cluster specifically expressed Lepr and Ctgf as well as high levels of Aspn, Sfrp1, and Fbln1, and we labeled them as Lepr-CBFs (Figure 1D). The characteristic CBF gene profile (Figure 1C), along with an absence of Pi16-CBFs markers, suggested Lepr-CBFs are located in the lamina propria close to the crypt/gland base as previously shown for intestinal fibroblasts expressing Lepr (Deng et al, 2022;Manieri et al, 2023).…”

Section: Enrichment Of St2 + Fibroblasts In Pjs Polypssupporting

confidence: 77%

Identification of a targetable ST2-expressing fibroblast subset driving Peutz-Jeghers syndrome polyposis

Domènech-Moreno,

Lim,

Brandt

et al. 2023

Preprint

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Inactivating germline mutations in the tumor suppressor kinaseLKB1(STK11) predispose to Peutz-Jeghers Syndrome (PJS) with increased cancer risk and early-onset development of gastrointestinal polyps requiring regular surveillance. Studies using PJS mouse models have indicated fibroblasts as drivers of polyp formation. Here, we use single-cell RNA sequencing to investigate the fibroblast heterogeneity and tumorigenic mechanisms in a PJS mouse model. We identify five distinct gastric fibroblast subsets, including a polyp-enriched ST2 (Il1rl1)-expressing crypt top fibroblast (CTF) cluster, and show that the polyps arise fromFoxl1-expressing CTFs. The transcriptional signature of the ST2+fibroblasts overlapped with the effects seen by LKB1 lossin vitroandin vivo. The ST2+fibroblasts also shared similarities with inflammation-associated fibroblasts, and inflammation exacerbated polyposis. Interestingly, the tumorigenic ST2+fibroblasts showed a distinct signaling pattern, including high expression of interleukin 11 (IL-11). Notably, IL-11 was required for the LKB1 loss-induced transcriptional changes in fibroblasts, and treatment with an IL-11 neutralizing antibody substantially reduced the tumor burden in the PJS mouse model, suggesting therapeutic value. In summary, our study uncovers a critical mechanism underlying PJS polyposis and suggests that PJS patients could benefit from anti-IL-11 therapy.

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Section: Enrichment Of St2 + Fibroblasts In Pjs Polypssupporting

confidence: 77%

Identification of a targetable ST2-expressing fibroblast subset driving Peutz-Jeghers syndrome polyposis

Domènech-Moreno,

Lim,

Brandt

et al. 2023

Preprint

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FGFR2 is essential for salivary gland duct homeostasis and MAPK-dependent seromucous acinar cell differentiation

Aure,

Symonds,

Villapudua

et al. 2023

Nat Commun

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Exocrine acinar cells in salivary glands (SG) are critical for oral health and loss of functional acinar cells is a major clinical challenge. Fibroblast growth factor receptors (FGFR) are essential for early development of multiple organs, including SG. However, the role of FGFR signaling in specific populations later in development and during acinar differentiation are unknown. Here, we use scRNAseq and conditional deletion of murine FGFRs in vivo to identify essential roles for FGFRs in craniofacial, early SG development and progenitor function during duct homeostasis. Importantly, we also discover that FGFR2 via MAPK signaling is critical for seromucous acinar differentiation and secretory gene expression, while FGFR1 is dispensable. We show that FGF7, expressed by myoepithelial cells (MEC), activates the FGFR2-dependent seromucous transcriptional program. Here, we propose a model where MEC-derived FGF7 drives seromucous acinar differentiation, providing a rationale for targeting FGFR2 signaling in regenerative therapies to restore acinar function.

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Defining the structure, signals, and cellular elements of the gastric mesenchymal niche

Cited by 2 publications

References 65 publications

Identification of a targetable ST2-expressing fibroblast subset driving Peutz-Jeghers syndrome polyposis

Identification of a targetable ST2-expressing fibroblast subset driving Peutz-Jeghers syndrome polyposis

FGFR2 is essential for salivary gland duct homeostasis and MAPK-dependent seromucous acinar cell differentiation

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