Oral Presentation 6th Australian Health and Medical Research Congress 2012

Cytotoxic therapies significantly alter the composition of the cells comprising murine haematopoietic stem cell niches. (#160)

Julie Quach 1 , Maria Askmyr 1 , Tanja Jovic 1 , Hannah King 1 , Emma Baker 1 2 , Nicole Walsh 1 2 , Louise E Purton 1 2
  1. St Vincent's Institute, Fitzroy, VIC, Australia
  2. Dept of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia

Murine haematopoietic stem cells (HSCs) are regulated within the bone marrow (BM), in anatomical locations termed HSC niches. Cytotoxic therapies used for treatment of cancer are known to dramatically affect haematopoiesis, however, the response of important niche regulators of HSCs to cancer therapies are largely unknown. Using adult male mice, we have extensively analysed the effects of irradiation or chemotherapy on HSC niche cells. Our studies have initially focused on the following putative HSC niche cell types: endothelial cells (ECs), adipocytes, mesenchymal stem and progenitor cells (MSPCs), osteoblasts (Obs) and osteoclasts (Ocs).

The earliest anatomical change observed was to ECs: the BM vessel structures were disorganised and the vessels were extremely dilated at early time points in response to all therapies, although vessel number was largely unchanged. Interestingly, the vasculature changes were transient and were restricted to sinusoids, as arteries were unaltered.

Adipocytes significantly increased between days 7-35 post-therapy. While these changes were only transient in response to chemotherapy, adipocyte numbers remained elevated long-term in mice that were irradiated and transplanted. The numbers of MSPCs increased at early time points post-therapy but showed altered fate commitment from osteoblast to adipocyte differentiation.

Ob numbers were slightly elevated in the trabecular bone region between days 4 and 10 of therapy. This was accompanied by significant increases in the numbers of Ocs, with an overall net loss of bone in the trabecular region; this bone loss persisted long-term. Inhibition of Ocs by a single dose of the bisphosphonate, zoledronic acid (ZA) prevented the bone loss, but in contrast to recent reports, did not significantly impair HSC numbers or function. In our study, bone mass was not elevated above normal levels in response to ZA, whereas mice in the other studies were osteopetrotic when analysed for HSCs.

In conclusion, niche cells that regulate HSCs are highly susceptible to cytotoxic therapies. Treatments aiding recovery of these HSC niche cells might improve HSC self-renewal and promote more rapid haematological recovery after cancer therapies.