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 Pnx1 gene promoter,respectively.These experiments demonstrate that following muscle injury,SCI causes the upregulation of PDGFRa 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.PDGFRa+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.

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;Fra?ois Genêt;Marie-Carline Le Bousse-Kerdilès;Sébastien Banzet;Jean-Pierre Lévesque

Mater Research Institute—The University of Queensland,Woolloongabba,QLD,Australia;Institut de Recherche Biomédicale des Armées(IRBA),INSERM UMRS-MD,1197 Clamart,France;INSERM UMRS-MD 1197,Université de Paris-Saclay,H?pital Paul Brousse,Villejuif ,France;INSERM UMS-44,Université de Paris-Saclay,H?pital Paul Brousse,Villejuif,France;UPOH(Unité Péri Opératoire du Handicap,Perioperative Disability Unit),Physical and Rehabilitation Medicine department,Raymond-Poincaré Hospital,Assistance Publique-H?pitaux de Paris(AP-HP),Garches,France;Université de Versailles Saint Quentin en Yvelines,UFR Simone Veil-Santé,END:ICAP INSERM U1179,Montigny le Bretonneux,France

骨研究（英文版）

[1]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;Fra?ois Genêt;Marie-Carline Le Bousse-Kerdilès;Sébastien Banzet;Jean-Pierre Lévesque-.Spinal cord injury reprograms muscle fibroadipogenic progenitors to form heterotopic bones within muscles)[J].骨研究（英文版）,2022(02):310-325

reprograms,fibroadipogenic,ossifications,NHOs,SCIs,FAPs,Pnx1,PDGFRa,Prrx1,NHO,PDGFRa+mesenchymal,CD56+myogenic

Spinal,cord,injury,progenitors,heterotopic,bones,within,muscles,cells,origin,neurogenic,which,develop,frequently,periarticular,following,spinal,injuries,traumatic,brain,remain,unclear,because,skeletal,harbors,two,populations,satellite,SCs,are,Lineage,tracing,experiments,using,Cre,recombinase,LoxP,system,were,performed,mouse,strains,fluorescent,protein,ZsGreen,specifically,expressed,either,Pax7,promoter,respectively,These,demonstrate,that,causes,upregulation,expression,but,not,failure,regenerate,myofibers,injured,reduced,apoptosis,continued,proliferation,resident,enabling,their,osteogenic,differentiation,into,No,expressing,detected,blood,after,suggesting,locally,derived,from,We,validated,these,findings,human,biopsies,isolated,surrounding,could,ectopic,when,transplanted,immunocompromised,mice,whereas,had,much,lower,potential,Therefore,pathology,undergo,uncontrolled,osteoblasts

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