Oncostatin m secreted from activated macrophages contributes to the development of neurogenic heterotopic ossifications with hematopoietic stem cell niches

Introduction/Background Heterotopic ossifications (HO) are characterized by the formation of ectopic bone in soft tissues generally in muscles surrounding joints. The risk of HOs is increased after spinal cord or brain injuries (neurogenic HO, NHO). Patients with HO suffer from pain and the range of motion from limbs with ectopic bone is highly reduced. Currently, the only effective treatment for HOs is surgery but recurrences are frequent, underpinning that a better understanding of its pathophysiology is required to cure patients. We investigated whether NHOs contain ectopic hematopoietic stem cell (HSC) niches and their mechanisms of formation in human and a murine model. Material and method NHOs and muscles surrounding NHOs from 64 patients (Garches Hospital, France) and a spinal cord injury (SCI) mouse model of NHO that we previously developed [1] were used. Results We first showed that human NHO marrow are HSC niches since they contained CD45 + CD34 + CD38 − cells capable to reconstitute in vivo human hematopoiesis in immunodeficient NSG mice. Human NHO marrow was also composed of functional mesenchymal stromal cells (MSCs) able to support in vitro long-term human hematopoiesis and in vivo murine hematopoiesis and of endothelial progenitors. OSM plasma concentrations were significantly elevated in human NHO patients. OSM was produced by CD14 + monocytes/macrophages from NHOs (NHO-mac) when stimulated with LPS. Conditioned media from LPS-stimulated NHO-mac significantly enhanced the osteogenic potential of muscle-derived stromal cells surrounding NHOs, an effect that was reversed by neutralizing anti-OSM antibody. In our SCI mouse model of NHO [1] , we show that OSM was significantly increased in damaged muscles. Interestingly, the bone volume of NHO was reduced in Osmr −/− mice. Conclusion Altogether, our results suggest that OSM secreted from macrophages contributes to NHO with HSC niches, and that OSM or OSMR could be suitable therapeutic targets.