Neuregulin1 is a key niche signal that supports intestinal stem cell proliferation

Jarde T1,2,3, Rossello F1,2,4, Kurian Arackal T1,2, Flores T1,2, Giraud M1,2, Prasko M1,2, Nefzger CM1,2,4, Abe S5, Polo JM1,2,4 and Abud HE1,2

  1. Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
  2. Cancer Program, Monash Biomedicine Discovery Institute, Clayton, Australia.
  3. Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Australia.
  4. Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
  5. Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, Kumamoto, Japan.

Identifying strategies to enhance intestinal stem cell proliferation may enable regeneration of the epithelium to be manipulated in degenerative diseases and intestinal pathologies. Using intestinal organoids grown ex vivo, we have defined Neuregulin1/ErbB signalling as a strong driver of cell proliferation in the intestinal epithelium. We defined the localisation of Neuregulin1 and interacting receptors in the small intestine using immunofluorescence and qRT-PCR. We observed that supporting niche cells express Neuregulin1, while stem cells express ErbB receptors, supporting a model where Neuregulin1/ErbB signalling directly regulates stem cells. The role of Neuregulin1 was also investigated in vivo using both a gene knockout approach and a model where activation of Neuregulin1/ErbB signalling was achieved in mice injected with 15ug Nrg1 for 5 days. Elevation of signalling increased cell proliferation in crypts, altered cellular differentiation and promoted regeneration. Loss of Neuregulin1 resulted in a significant decrease in cell proliferation within crypts in both stem and progenitor cells. The molecular changes induced by Neuregulin1 were examined using RNA sequencing which defined a proliferative molecular signature in both stem and progenitor cells. This was reinforced by examining the ability of single intestinal stem cells to generate organoids. Neuregulin1 significantly promotes organoid growth and the formation of colonies from single stem cells.