1022 - Macrophages are Essential Regulators of Hematopoietic and Bone Tissues

Abstract

Macrophages are dispersed throughout the bone marrow (BM) and present at the endosteum and periosteum. Macrophages are key regulators of the bone tissue and hematopoietic stem and progenitor cell (HSPC) niches. Therapeutic administration of G-CSF causes the collapse of HSPC niche function with reduced expression of HSPC-supportive niche factors resulting in HSPC mobilization into the blood together with an arrest in endosteal bone formation. We and others have shown that these effects are mediated in part by BM macrophages. Indeed G-CSF supresses several BM macrophage subsets and various methods to deplete macrophage subsets lead to similar collapse of HSPC niche function and HSPC mobilization. The HSPC niche-supporting role of macrophages is confirmed by the facts that G-CSF causes similar collapse of HSPC niches and HSPC mobilization in mice expressing its receptor solely in macrophages / monocytes but not in granulocytes. Reciprocally, we find that a subset of BM-resident CD169+ macrophages is essential for HSC engraftment following lethal irradiation. These host-derived BM macrophages are radio-resistant, divide autonomously following lethal irradiation and HSC transplant, are necessary for optimal HSC engraftment and cannot be replaced by donor HSC-derived macrophages / monocytes to ensure HSC engraftment. The bone is also critically dependent on macrophages. Both endosteum and periosteum are lined by a canopy of specialized macrophages above the layer of active osteoblasts. These “osteomacs” are necessary to maintain osteoblast differentiation and function. We have recently shown that similar to HSPC niche supportive macrophages, osteomacs express CD169, are depleted in response to G-CSF and required for bone repair following fractures. Finally we have recently shown that macrophages/ monocytes are essential to the pathological formation of ectopic bones and HSPC niches. Heterotopic ossification is a frequent pathology in patients suffering traumatic brain or spinal cord injury (SCI). They form in the periarticular muscles and can completely ankylose the affected joints. These debilitating “neurogenic” heterotopic ossifications (NHO) contain a functional hematopoietic BM with HSC capable of hematopoietic engraftment in transplanted mice. In a mouse model of SCI-Induced NHO that we have developed, we have found that macrophages/monocytes are key drivers of these NHO in part via oncostatin M secreted by macrophages. In conclusion macrophages are key regulators of haematopoiesis and bone tissue and key drivers of the pathological formation of ectopic bones and HSPC niches.