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.

神经源性异位骨化 (NHO) 的起源细胞经常在脊髓损伤 (SCI) 和创伤性脑损伤后的关节周围肌肉中发育，但仍不清楚，因为骨骼肌有两个祖细胞群：卫星细胞 (SC)，它们是肌源性和纤维脂肪源性祖细胞 (FAP)，它们是间充质的。使用 Cre 重组酶/LoxP 系统的谱系追踪实验在两种小鼠品系中进行，荧光蛋白ZsGreen 在Pax7或Prrx1的控制下在骨骼肌的 SCs 或 FAPs 中特异性表达基因启动子，分别。这些实验表明，肌肉损伤后，SCI 会导致 FAPs 上 PDGFRα 表达上调，但 SCs 不会上调，并且 SCs 无法在受伤肌肉中再生肌纤维，细胞凋亡减少和肌肉驻留 FAPs 的持续增殖使其成骨分化为 NHOs。在损伤后的血液中未检测到在Prrx1启动子下表达ZsGreen的细胞，这表明 NHOs 起源的细胞局部来源于受伤的肌肉。我们使用人类 NHO 活检验证了这些发现。从 NHO 活检组织周围的肌肉中分离出的PDGFRα ^{+间充质细胞在移植到免疫功能低下的小鼠体内时可以形成异位人骨，而 CD56 +}肌原细胞的潜力要低得多。因此，NHO 是一种损伤肌肉的病理学，其中 SCI 将 FAP 重新编程以进行不受控制的增殖和分化为成骨细胞。