Why macrophages promote heterotopic ossifications following spinal cord injuries (2016–2018)

This project aims to understand how the nervous system and macrophages together regulate mesenchymal stem cell differentiation in muscles. Understanding this relationship is particularly important as it is the dysregulation of this normal regeneration process that leads to the formation of heterotopic bones in inflamed muscles. This phenomenon, called neurological heterotopic ossification (NHO), is observed in ~20% of patients with traumatic spinal cord (SCI) or brain injuries. We have published a novel mouse model which shows that a combination of both SCI and muscular inflammation is required for the development of NHO. Our model also reveals that macrophages in the injured muscles are critical drivers of SCI-induced NHO (SCI-NHO), and that TNF-¿¿, IL-1¿¿, CSF-1 and oncostatin M are overexpressed in the inflamed muscles of SCI mice, and may be key drivers of NHO development. The central hypothesis is that SCI alters macrophage activation in inflamed muscles and biases their polarization towards a pro-osteogenic function. As a consequence, macrophages that normally support myogenic repair now promote osteoblast differentiation and SCI-NHO. This will be investigated with the following specific aims: 1) Determine the effect of SCI on macrophage activation and their secretome in inflamed muscles. 2) Investigate the role of macrophage-mediated pathways in muscle injury that are abnormally activated by SCI. 3) Determine if autonomic dysfunction drives abnormal macrophage activation and NHO. This project will identify potential molecular mechanisms of NHO advancing basic knowledge in stem cell biology as it illustrates how deregulation of the cross-talk between nervous and immune systems after SCI leads to pathological osteogenic differentiation of muscle cells instead of muscle repair. As we are the 1st group to have developed an animal model of non-genetic SCI-NHO, we are in a leading position to identify novel therapeut...
Grant type:
NHMRC Project Grant
Funded by:
National Health and Medical Research Council