Oral Presentation ASSCR, AGCTS, ISCT ANZ and Friends Joint Scientific Conference 2019

Neuregulin 1 promotes intestinal stem cell proliferation and improves tissue regeneration following damage (#32)

Thierry Jarde 1 2 3 , Fernando J Rossello 1 4 5 , Wing Hei Chan 1 2 , Teni Kurian Arackal 1 2 , Tanvir Kahlon 1 2 , Tracey Flores 1 2 , Mégane Giraud 1 2 , Elizabeth Richards 1 2 , Eva Chan 1 2 , Mirsada Prasko 1 2 , Jacqueline F Donoghue 3 6 , Shin-ichi Abe 7 , Toby J Phesse 8 , Christian M Nefzger 1 2 4 9 , Jose M Polo 1 2 4 , Helen E Abud 1 2
  1. Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
  2. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  3. Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
  4. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
  5. University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia
  6. Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Melbourne, VIC, Australia
  7. Center for Education, Kumamoto Health Science University, Kumamoto, Japan
  8. European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United-Kingdom
  9. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia

Identifying signals that regulate intestinal stem cell (ISCs) proliferation may enable stem cell pools to be manipulated in degenerative diseases and intestinal pathologies. A molecule which holds promise to support ISC-mediated tissue regeneration is the growth factor Neuregulin 1 (Nrg1).

We examined the expression of Nrg1 and its receptors in the small intestine using immunofluorescence and qRT-PCR. We observed that supporting niche cells express Nrg1, while ISCs express ErbB receptors, supporting a model where Nrg1/ErbB signalling directly regulates ISCs.

We investigated the role of Nrg1 in vivo using both an inducible gene knockout approach and a model where activation of Nrg1 signalling was achieved by injecting mice with 15ug Nrg1 for 5 days. Elevation of signalling increased intestinal cell proliferation and altered cellular differentiation. The molecular changes induced by Nrg1 treatment were examined using RNA sequencing which defined a strong impact on the cell cycle and conversion of progenitor cells to an intestinal stem cell identity. Loss of Nrg1 resulted in a significant decrease in cell proliferation in both stem and progenitor cells.

Using two mouse models of injury/regeneration (irradiation and 5-FU-induced damage), we observed that the expression of Nrg1 was 5-10 fold increased during the intestinal regenerative phase. Importantly, loss of Nrg1 dramatically impaired intestinal tissue regeneration following injury. In contrast, the regenerative response was significantly improved when mice were treated with Nrg1. This was reinforced by using an in vitro model of regeneration; Nrg1 significantly promoted organoid growth and the formation of colonies from single ISCs.

Overall, our results demonstrate Nrg1 is a potent niche signal that drives proliferation and regulates ISC identity.

  • Have you presented your abstract at another international meeting?: No