Spinal cord injury reprograms muscle fibroadipogenic progenitors to form heterotopic bones within muscles
Hsu-Wen Tseng,
Dorothée Girard,
Kylie A. Alexander,
Susan M. Millard,
Frédéric Torossian,
Adrienne Anginot,
Whitney Fleming,
Jules Gueguen,
Marie-Emmanuelle Goriot,
Denis Clay,
Beulah Jose,
Bianca Nowlan,
Allison R. Pettit,
Marjorie Salga,
François Genêt,
Marie-Caroline Le Bousse-Kerdilès,
Sébastien Banzet,
Jean-Pierre Lévesque
Affiliations
Hsu-Wen Tseng
Mater Research Institute—The University of Queensland
Dorothée Girard
Institut de Recherche Biomédicale des Armées (IRBA), INSERM UMRS-MD
Kylie A. Alexander
Mater Research Institute—The University of Queensland
Susan M. Millard
Mater Research Institute—The University of Queensland
Frédéric Torossian
INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse
Adrienne Anginot
INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse
Whitney Fleming
Mater Research Institute—The University of Queensland
Jules Gueguen
Institut de Recherche Biomédicale des Armées (IRBA), INSERM UMRS-MD
Marie-Emmanuelle Goriot
Institut de Recherche Biomédicale des Armées (IRBA), INSERM UMRS-MD
Denis Clay
INSERM UMS-44, Université de Paris-Saclay, Hôpital Paul Brousse
Beulah Jose
Mater Research Institute—The University of Queensland
Bianca Nowlan
Mater Research Institute—The University of Queensland
Allison R. Pettit
Mater Research Institute—The University of Queensland
Marjorie Salga
UPOH (Unité Péri Opératoire du Handicap, Perioperative Disability Unit), Physical and Rehabilitation Medicine department, Raymond-Poincaré Hospital, Assistance Publique – Hôpitaux de Paris (AP-HP)
François Genêt
UPOH (Unité Péri Opératoire du Handicap, Perioperative Disability Unit), Physical and Rehabilitation Medicine department, Raymond-Poincaré Hospital, Assistance Publique – Hôpitaux de Paris (AP-HP)
Marie-Caroline Le Bousse-Kerdilès
INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse
Sébastien Banzet
Institut de Recherche Biomédicale des Armées (IRBA), INSERM UMRS-MD
Jean-Pierre Lévesque
Mater Research Institute—The University of Queensland
Abstract 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/LoxP system were performed in two mouse strains with the fluorescent protein ZsGreen 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 ZsGreen 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.
