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