Bone marrow SELENOP⁺ macrophages support hematopoiesis after transplantation via GAS6-AXL signaling pathway

Poor hematopoietic reconstitution (PHR), a serious complication after chemotherapy or radiotherapy in patients with hematological or solid malignancies, which lacks effective treatment options because its underlying pathogenesis remains unclear. Bone marrow macrophages (BM MΦs) are multifunctional, plastic cells essential in hematopoiesis though our previous study demonstrated distinct hematopoietic regulatory role between M1 and M2 subtypes. However, the specific phenotype of M2-MΦ and pathways involved in hematopoietic support remain unclear. Here, we identified a novel population of BM-MΦs, SELENOP⁺ MΦs, that exhibit an M2-biased phenotype with hematopoietic stem cell (HSC)-supporting ability. These cells were markedly impaired in patients with poor graft function (PGF) after allogeneic HSC transplantation, potentially because of defective autocrine GAS6-AXL (ligand-receptor) signaling. Both in vitro and BM MΦ-specific AXL knockdown mouse models confirmed that reduced AXL activity contributed to MΦ dysfunction and the downstream reduction in IGF1 secretion. Notably, treatment with GAS6 partially restored the HSC-supporting ability of impaired BM MΦ from PGF patients in vitro. Overall, our study identified an HSC-supportive SELENOP⁺ MΦ subset regulated by GAS6-AXL signaling, offering novel therapeutic insights for impaired hematopoiesis.