Oral Presentation Australian Society for Medical Research Annual Scientific Meeting 2016

Prostaglandin I2 in the bone marrow niche protects haematopoietic stem cell from irradiation stress (#3)

Joshua Tay 1 , Jean-Pierre Levesque 2 3 , Falak Helwani 1 , Gareth Price 4 , Bianca Nowlan 5 , Valerie Barbier 1 , Ingrid Winkler 1
  1. Stem Cell & Cancer Group, Mater Research, Brisbane, QLD, Australia
  2. Stem Cell Biology group, Mater Research, Brisbane, QLD, Australia
  3. School of Medicine, University of Queensland, Brisbane, QLD, Australia
  4. Individualising Medical Care Group, Mater Research, Brisbane, QLD, Australia
  5. Stem Cell Therapies group, QUT-IHBI, Brisbane, QLD, Australia

Introduction. Haematopoietic stem cells (HSCs) regenerate the blood and immune system and are regulated by their immediate microenvironment or niche. The most potent functional HSCs are enriched at the endosteum near the bone, which comprises ~10% of total bone marrow (BM). Many niche factors interact with and regulate HSCs locally, both in homeostasis and regeneration, many of which remain to be elucidated.

Objective. To identify novel factors that regulate HSC function, we compared endosteal and central BM mRNA using gene expression microarray and validated it with qRT-PCR.

Results. Our findings that prostaglandin I2 (PGI2) synthase mRNA expression is enriched ~10-fold in the endosteum and that the canonical PGI2 receptor IPĀ is expressed on BM haematopoietic stem and progenitor cells (HSPCs) prompted us to examine their function. We administered the stable PGI2 analogue iloprost to mice, due to the lability of PGI2. In steady state, iloprost administration did not alter BM HSPC phenotypes by flow cytometry nor HSC self-renewal as measured using gold standard serial long term competitive repopulation transplant assay compared to vehicle controls. To test the effect of iloprost following irradiation stress, mice were sub-lethally irradiated and administered iloprost for 4 days. At 21 days post-irradiation, iloprost treatment partially rescued HSC short term self-renewal (n=8, p<0.05). We also found that 3 days administration of iloprost before irradiation diminished reactive oxygen species levels in HSCs to 40% of vehicle control levels (n=5, p<0.05), suggesting that PGI2 elicits its radioprotective effects at least partially via mitigating harmful reactive oxygen species accumulation.

Conclusion. Together these data suggest that PGI2 produced in BM niches play a novel role in the regulation of HSC, especially following stress. PGI2 analogues are clinically approved and could be trialled to reduce radiation sickness and alleviate some of the severe side effects of therapeutic irradiation.