| First Author | Scharr M | Year | 2026 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 20 |
| Issue | 2 | Pages | 101642 |
| PubMed ID | 40998011 | Mgi Jnum | J:372723 |
| Mgi Id | MGI:8249736 | Doi | 10.1016/j.jcmgh.2025.101642 |
| Citation | Scharr M, et al. (2025) R-Spondin1 regulates fate of enteric neural progenitors via differential LGR4/5/6-expression in mice and humans. Cell Mol Gastroenterol Hepatol :101642 |
| abstractText | BACKGROUND & AIMS: Regeneration and cytodifferentiation of various adult epithelial stem cell compartments are controlled by the WNT-agonist R-Spondin1 (RSPO1) and the Leucin-rich-repeat-containing G-protein-coupled-receptors (LGR4/5/6). We hypothesized that RSPO1-LGR-signaling is also involved in regulating neuroregeneration and homeostasis of the postnatal enteric nervous system (ENS). METHODS: We isolated neural crest-derived ENS-cells from wnt1-tomato mice and patient samples, which were evaluated using pharmacological in vitro studies under RSPO1 stimulation. We use proliferation assays (BrdU-incorporation, Ki67-staining), as well as neuronal differentiation screenings. We performed FACS-based in vitro assays to stratify human ENS-cells for LGR-receptor expression, and to characterize them by immunofluorescence co-labeling studies in vivo. RESULTS: If applied to murine and human ENS-progenitors, RSPO1 led to an increased proliferation (P=.002), followed by enhanced enteric neurogenesis (P<.001). This coincided with an upregulation of LGR4 expression during ENS-progenitor proliferation (P</=.001) in vitro. In contrast, we observed a reduced proliferation in ENS-progenitors expressing LGR5 (P</=.001), while LGR6 was not expressed by proliferative ENS-progenitors (P</=.05). Instead, LGR5 and LGR6 expression increased over the course of induced neuronal differentiation (LGR5: P</=.001 and LGR6: P</=.05), consistent with the in vivo expression. CONCLUSIONS: LGR-receptor expression therefore might represent a previously unknown mechanism influencing the fate decision of ENS-progenitor cells between proliferation and neuronal differentiation. Thus, our study is essential for our understanding of regenerative aspects of the postnatal ENS in health and disease. |
