Mesenchymal Niche-Derived Neuregulin-1 Drives Intestinal Stem Cell Proliferation and Regeneration of Damaged Epithelium
Thierry Jard, Wing Hei Chan, Fernando J Rossello, Tanvir Kaur Kahlon, Mandy Theocharous, Teni Kurian Arackal, Tracey Flores, Megane Giraud, Elizabeth Richards, Eva Chan, Genevieve Kerr, Rebekah M Engel, Mirsada Prasko, Jacqueline F Donoghue, Shin-ichi Abe, Toby J Phesse, Christian M Nefzger, Paul J McMurrick, David R Powell, Roger J Daly Show all
Cell Stem Cell | CELL PRESS | Published : 2020
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 activ..View full abstract
Awarded by NHMRC Australia
Awarded by MRC, UK
The authors acknowledge the resources and staff of the BDI Organoid Program, Micro Imaging, Flowcore, MARP, and Histology platforms at Monash University, Victoria, Australia. We also thank the ACRF Centre for Cancer Genomic Medicine at the MHTP Medical Genomics Facility (Clayton, Australia) and Dr. Chappaz for help with flow cytometry. This work is supported by NHMRC Australia grants 1129600 (T.J.), 1011187, 1100531 (H.E.A.), and 1188689 (H.E.A. and T.J.); a Monash University grant (T.J. and H.E.A.); MRC, UK, MR/R026424/1 (T.J.P.); BLS/CMU Fellowship (T.J.P.); Sylvia and Charles Senior Medical Viertel Fellowship (J.M.P.); a Monash BDI scholarship (E.C.); and an RTP scholarship (T.K.K.). We thank Prof. Hans Clevers for helpful discussions.