Mesenchymal niche-derived neuregulin-1 drives intestinal stem cell proliferation and regeneration of damaged epithelium

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dc.contributor.authorJardé, T.
dc.contributor.authorChan, W.H.
dc.contributor.authorRossello, F.J.
dc.contributor.authorKaur Kahlon, T.
dc.contributor.authorTheocharous, M.
dc.contributor.authorKurian Arackal, T.
dc.contributor.authorFlores, T.
dc.contributor.authorGiraud, M.
dc.contributor.authorRichards, E.
dc.contributor.authorChan, E.
dc.contributor.authorKerr, G.
dc.contributor.authorEngel, R.M.
dc.contributor.authorPrasko, M.
dc.contributor.authorDonoghue, J.F.
dc.contributor.authorAbe, S.I.
dc.contributor.authorPhesse, T.J.
dc.contributor.authorNefzger, C.M.
dc.contributor.authorMcMurrick, P.J.
dc.contributor.authorPowell, D.R.
dc.contributor.authorDaly, R.J.
dc.contributor.authoret al.
dc.date.issued2020
dc.description.abstractEpidermal 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.
dc.description.statementofresponsibilityThierry Jarde, Wing Hei Chan, Fernando J. Rossello, Tanvir Kaur Kahlon, Mandy Theocharous, Teni Kurian Arackal, Tracey Flores, Mégane 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, Jose M. Polo, and Helen E. Abud
dc.identifier.citationCell Stem Cell, 2020; 27(4):646-662.e7
dc.identifier.doi10.1016/j.stem.2020.06.021
dc.identifier.issn1934-5909
dc.identifier.issn1875-9777
dc.identifier.orcidPolo, J.M. [0000-0002-2531-778X]
dc.identifier.urihttps://hdl.handle.net/2440/133649
dc.language.isoen
dc.publisherElsevier BV
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1129600
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1011187
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1100531
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1188689
dc.rights© 2020 Elsevier Inc.
dc.source.urihttps://doi.org/10.1016/j.stem.2020.06.021
dc.subjectCell proliferation
dc.subject.meshIntestines
dc.subject.meshPaneth Cells
dc.subject.meshEpithelium
dc.subject.meshNeuregulin-1
dc.subject.meshCell Proliferation
dc.titleMesenchymal niche-derived neuregulin-1 drives intestinal stem cell proliferation and regeneration of damaged epithelium
dc.typeJournal article
pubs.publication-statusPublished

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