Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment

Simranpreet Kaur, Liza J Raggatt, Susan M Millard, Andy C Wu, Lena Batoon, Rebecca N Jacobsen, Ingrid G Winkler, Kelli P MacDonald, Andrew C Perkins, David A Hume, Jean-Pierre Levesque, Allison R Pettit

Distinct subsets of resident tissue macrophages are important in hematopoietic stem cell niche homeostasis and erythropoiesis. We used a myeloid reporter gene (Csf1r-eGFP) to dissect the persistence of bone marrow and splenic macrophage subsets following lethal irradiation and autologous hematopoietic stem cell transplantation in a mouse model. Multiple recipient bone marrow and splenic macrophage subsets survived post-autologous hematopoietic stem cell transplantation with organ specific persistence kinetics. Short-term persistence (5 weeks) of recipient resident macrophages in spleen paralleled the duration of extra medullary hematopoiesis. In bone marrow, radiation-resistant recipient CD169+ resident macrophages and erythroid-island macrophages self-repopulated long-term post transplantation via autonomous cell division. Post-transplant peak expansion of recipient CD169+ resident macrophage number in bone marrow aligned with the persistent engraftment of phenotypic long-term reconstituting hematopoietic stem cell within bone marrow. Selective depletion of recipient CD169+ macrophages significantly compromised the engraftment of phenotypic long-term reconstituting hematopoietic stem cells and consequently impaired hematopoietic reconstitution. Recipient bone marrow resident macrophages are essential for optimal hematopoietic stem cell transplantation outcomes and could be an important consideration in development of pre-transplant conditioning therapies and/or chemo-resistance approaches.