The cells of origin of neurogenic heterotopic ossifications(NHOs), which develop frequently in the periarticular muscles following spinal cord injuries(SCIs) and traumatic brain injuries, remain unclear because skelet...The cells of origin of neurogenic heterotopic ossifications(NHOs), which develop frequently in the periarticular muscles following spinal cord injuries(SCIs) and traumatic brain injuries, remain unclear because skeletal muscle harbors two progenitor cell populations: satellite cells(SCs), which are myogenic, and fibroadipogenic progenitors(FAPs), which are mesenchymal. Lineage-tracing experiments using the Cre recombinase/Lox P system were performed in two mouse strains with the fluorescent protein Zs Green specifically expressed in either SCs or FAPs in skeletal muscles under the control of the Pax7 or Prrx1 gene promoter, respectively. These experiments demonstrate that following muscle injury, SCI causes the upregulation of PDGFRα expression on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHOs. No cells expressing Zs Green under the Prrx1 promoter were detected in the blood after injury, suggesting that the cells of origin of NHOs are locally derived from the injured muscle. We validated these findings using human NHO biopsies. PDGFRα+mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice, whereas CD56+myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to undergo uncontrolled proliferation and differentiation into osteoblasts.展开更多
基金partly supported by Project Grant 1101620 and Ideas Grant 1181053 from the National Health and Medical Research Council of Australia (NHMRC)by award W81XWH-15-1-0606 from the Congressionally Approved Spinal Cord Injury Research Program of the US Department of Defense+4 种基金by funds from the Mater Foundationsupported by Research Fellowship 1136130 from the NHMRCpartly funded by project grant 1101620 from the French Government Defense Procurement and Technology Agency (DGA – Direction Générale de l’Armement)The Translational Research Institute is partly funded by the Federal Government of Australiasupported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program
文摘The cells of origin of neurogenic heterotopic ossifications(NHOs), which develop frequently in the periarticular muscles following spinal cord injuries(SCIs) and traumatic brain injuries, remain unclear because skeletal muscle harbors two progenitor cell populations: satellite cells(SCs), which are myogenic, and fibroadipogenic progenitors(FAPs), which are mesenchymal. Lineage-tracing experiments using the Cre recombinase/Lox P system were performed in two mouse strains with the fluorescent protein Zs Green specifically expressed in either SCs or FAPs in skeletal muscles under the control of the Pax7 or Prrx1 gene promoter, respectively. These experiments demonstrate that following muscle injury, SCI causes the upregulation of PDGFRα expression on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHOs. No cells expressing Zs Green under the Prrx1 promoter were detected in the blood after injury, suggesting that the cells of origin of NHOs are locally derived from the injured muscle. We validated these findings using human NHO biopsies. PDGFRα+mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice, whereas CD56+myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to undergo uncontrolled proliferation and differentiation into osteoblasts.
