Mesenchymal Niche-Derived Neuregulin-1 Drives Intestinal Stem Cell Proliferation and Regeneration of Damaged Epithelium.

Cell Stem Cell
Thierry JardéHelen E Abud

Abstract

Epidermal growth factor (EGF) maintains intestinal stem cell (ISC) proliferation and is a key component of organoid growth media yet is dispensable for intestinal homeostasis, suggesting roles for multiple EGF family ligands in ISC function. Here, we identified neuregulin 1 (NRG1) as a key EGF family ligand that drives tissue repair following injury. NRG1, but not EGF, is upregulated upon damage and is expressed in mesenchymal stromal cells, macrophages, and Paneth cells. NRG1 deletion reduces proliferation in intestinal crypts and compromises regeneration capacity. NRG1 robustly stimulates proliferation in crypts and induces budding in organoids, in part through elevated and sustained activation of mitogen-activated protein kinase (MAPK) and AKT. Consistently, NRG1 treatment induces a proliferative gene signature and promotes organoid formation from progenitor cells and enhances regeneration following injury. These data suggest mesenchymal-derived NRG1 is a potent mediator of tissue regeneration and may inform the development of therapies for enhancing intestinal repair after injury.

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Citations

Dec 9, 2020·Nature Communications·Maria Antfolk, Kim B Jensen
Jan 6, 2021·International Journal of Molecular Sciences·Ken KurokawaKazuhiko Koike
Mar 5, 2021·EMBO Molecular Medicine·Amanpreet KaurBabita Madan
Dec 6, 2020·Cell Stem Cell·Emily M HollowayJason R Spence
Jul 3, 2021·Nutrients·Kanta Chandwe, Paul Kelly
Aug 6, 2021·Frontiers in Cell and Developmental Biology·Helen E AbudThierry Jardé
Aug 20, 2021·Developmental Biology·Meng-Han WuChristopher M Cox
Jun 2, 2021·Current Opinion in Genetics & Development·Hjalte L Larsen, Kim B Jensen

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