Fibroblast-derived EGF ligand neuregulin 1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth

Abstract

Growth factors secreted by stromal fibroblasts regulate the intestinal epithelium. Stroma-derived Epidermal growth factor (EGF) family ligands are implicated in epithelial regeneration and tumorigenesis, but their specific contributions and associated mechanisms remain unclear. Here, we use primary intestinal organoids modeling homeostatic, injured, and tumorigenic epithelium to assess how fibroblast-derived EGF family ligands Neuregulin-1 (NRG1) and Epiregulin (EREG) regulate the intestinal epithelium. NRG1 was expressed exclusively in the stroma, robustly increased crypt budding and protected intestinal epithelial organoids from radiation-induced damage. NRG1 also induced regenerative features in the epithelium including a fetal-like transcriptome, suppression of the Lgr5+ stem cell pool, and remodeling of the epithelial actin cytoskeleton. Intriguingly, unlike EGF and EREG, NRG1 failed to support the growth of pre-tumorigenic intestinal organoids lacking the tumor suppressor Apc, commonly mutated in human colorectal cancer (CRC). Interestingly, high expression of stromal NRG1 was associated with improved survival in CRC cohorts, suggesting a tumor suppressive function. Our results highlight the power of stromal NRG1 in transcriptional reprogramming and protection of the intestinal epithelium from radiation injury without promoting tumorigenesis.

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

“…The signals to epithelial cells included NRG and HGF family ligands, while PTH was received by pericytes and IL-11 signal by fibroblasts (Figure 5B-C). Interestingly, analysis of the ligand-receptor pairs constituting the signaling patterns predicted HGF-MET and NRG1-ERBB3 as the most active pathways emanating from ST2-CTFs to epithelial cells, suggesting functional relevance as noted before in regenerative and tumor contexts (Joosten et al 2017; Jardé et al 2020; Lemmetyinen et al 2023) (Supplementary Figure 5B-C). FGF7-FGFR1 signaling was predicted to mainly target fibroblasts, while EREG-EGFR signaling was active to both epithelial cells and fibroblasts.…”

“…CTFs in the colon and intestine express differentiation-promoting ligands such as Bmp5 , Bmp7, Wnt5a, Nrg1, as well as the subepithelial telocyte marker Foxl1 (Aoki et al 2016; Shoshkes-Carmel et al 2018; Brügger et al 2020; McCarthy et al 2020; Lemmetyinen et al 2023). These ligands were highly expressed in our fibroblast clusters 3-5, indicating a CTF identity (Figure 1C).…”

An extra-genital cell population contributes to urethra closure during mouse penis development

“…NRG1 proteins signal through the receptor tyrosine kinases ERBB3 and ERBB4, and with less affinity to EGFR in several cell types (27). ERBB2 has no known ligand and mainly serves as a critical co-regulator for the other three EGF-related receptors (28).…”

“…NRG1 is commonly associated with cell migration in Schwann cells and neural crest cells (30). In intestinal organoids of epithelial cells, NRG1 treatment induced actin-cytoskeleton alternations, which caused increased budding and tube formation (27, 42). NRG1 signals mainly through receptors ERBB3 and ERBB4, which commonly heterodimerize with EGFR and ERBB2 to facilitate signaling (43).…”

Regionalized cell and gene signatures govern oesophageal epithelial homeostasis

“…In situ localization of Igf1 mRNA confirmed a distal stromal enrichment (Figure 6G). NRG1 belongs to the EGF growth factor family and mediates intestinal stem cell proliferation and regeneration potential 54,55 . We explored oesophageal NRG1-signaling, predicted to originate in the proximal oesophageal epithelium (Figure 6H).…”