Recipient bone marrow macrophages contribute to haematopoietic stem cell transplantation success (2016–2018)

Abstract:
The full potential and broader applicability of haematopoietic stem cell (HSC) transplantation is hampered by significant risks. Reducing the number of donor cells required for successful transplant and accelerating post-transplant haematopoietic reconstitution would greatly reduce HSC transplantation risk. We have previously shown that bone marrow (BM) resident macrophages (BM-Macs) are required for maintenance of HSC niches, the specialized environments within BM that support and instruct HSC. We now have preliminary data demonstrating that BM-Macs are resistant to a lethal, myeloablative radiation dose and persist long-term post-autologous HSC transplant. These resilient recipient-derived BM-Macs are located within endosteal perivascular niches and express a phenotype consistent with HSC niche macrophages. The recipient BM-Macs expand post-Tx and this increase correlates with expansion of donor-derived long-term repopulating HSC within BM. Finally, specific depletion of recipient BM-Macs 6 weeks post-transplant reduces reconstitution potential of engrafted HSC in a secondary competitive transplant assay. We hypotheses that: Recipient BM-Macs are required for reformation of HSC niches and BM engraftment of long-term repopulating HSC after autologous transplantation. Consequently, increasing the number and function of recipient BM-Macs post-Tx will increase the number of viable HSC niches, which in turn will accelerate and improve efficiency of HSC engraftment and haematopoietic reconstitution. We will test the hypotheses using 3 Aims that will determine: 1) the necessity of recipient BM-Macs for successful HSC transplantation, 2) identify the molecular mechanisms underpinning BM-Mac resilience, niche reformation function and HSC supportive roles, and 3) determine whether expanding BM-Macs using a novel chimeric colony stimulating factor-1 molecule, can improve HSC transplantation outcomes.
Grant type:
NHMRC Project Grant
Researchers:
Funded by:
National Health and Medical Research Council