Efferocytosis enhances macrophage pro-angiogenic functions for bone marrow regeneration.

Myeloablative treatments before bone marrow (BM) transplantation severely disrupt the microvasculature of the BM, and its regeneration precedes and supports hematopoietic regeneration after BM transplantation. Thus, the identification of factors that regulate BM vascular regeneration after an injury could offer a significant therapeutic opportunity to improve hematopoietic regeneration. After myeloablation, the BM cavity is filled with various dying cell-derived products. Here, we show that after transplantation, dying cell-derived products educate macrophages into a proangiogenic state and enhance vascular regeneration in the BM. Mechanistically, dying cell-derived sphingosine-1-phosphate (S1P) primes hypoxia-inducible factor-1α (HIF-1α) gene expression in macrophages. Importantly, our results revealed that the degradation of apoptotic bodies (ApoBDs) elevates intracellular cholesterol levels and activates their sensor, liver X receptor α (LXRα), in macrophages. Activated LXRα physically binds to the HIF-1α protein and inhibits its ubiquitylation, further potentiating VEGFA expression in macrophages. In vivo studies using transgenic mouse models and liposome-mediated delivery confirm that the LXRα/HIF-1α axis is required for macrophage-driven vascular repair following transplantation. These data not only uncover a new role for macrophages in BM vascular regeneration, but also provide novel evidence demonstrating the unexpected beneficial effect of efferocytosis in eliciting the pro-healing functions of macrophages in the context of injury.