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

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

  • Cell Stem Cell. 2020 Oct 1;27(4):646-662.e7. doi: 10.1016/j.stem.2020.06.021.
Thierry Jardé 1,  Wing Hei Chan 2,  Fernando J Rossello 3,  Tanvir Kaur Kahlon 2,  Mandy Theocharous 4,  Teni Kurian Arackal 2,  Tracey Flores 2,  Mégane Giraud 2,  Elizabeth Richards 2,  Eva Chan 2,  Genevieve Kerr 2,  Rebekah M Engel 5,  Mirsada Prasko 2,  Jacqueline F Donoghue 6,  Shin-Ichi Abe 7,  Toby J Phesse 8,  Christian M Nefzger 9,  Paul J McMurrick 10,  David R Powell 11,  Roger J Daly 4,  Jose M Polo 12,  Helen E Abud 13
Affiliations

Affiliations

  • 1 Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia. Electronic address: thierry.jarde@monash.edu.
  • 2 Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia.
  • 3 Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, VIC 3000, Australia.
  • 4 Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia; Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia.
  • 5 Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Cabrini Monash University Department of Surgery, Cabrini Hospital, Malvern, VIC 3144, Australia.
  • 6 Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; Department of Obstetrics and Gynaecology, Royal Women's Hospital, Melbourne University, Melbourne, VIC 3052, Australia.
  • 7 Center for Education, Kumamoto Health Science University, Kumamoto 861-5598, Japan.
  • 8 European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff CF24 4HQ, UK; Doherty Institute of Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
  • 9 Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
  • 10 Cabrini Monash University Department of Surgery, Cabrini Hospital, Malvern, VIC 3144, Australia.
  • 11 Monash Bioinformatics Platform, Monash University, Clayton, VIC 3800, Australia.
  • 12 Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
  • 13 Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia. Electronic address: helen.abud@monash.edu.
PMID: 32693086 DOI: 10.1016/j.stem.2020.06.021
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.

Keywords

EGF; ERBB3; PDGFRα+ stromal cells; cell proliferation; intestinal stem cells; macrophages; neuregulin 1; niche; stem cell identity; tissue regeneration.

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