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<p>Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder caused by gain-of-function mutations in ACVR1/ALK2, leading to progressive heterotopic ossification (HO) through endochondral bone formation. Inflammatory flare-ups often precede new ossification events, but the cellular and molecular mechanisms linking immune responses to progenitor cell fate remain incompletely understood. Here, using a tamoxifen-inducible Acvr1R206H mouse model of FOP and a reproducible muscle injury protocol, we combined single-cell RNA sequencing with <i>in vitro </i>assays to dissect early events during lesion formation. We identified an expansion of macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in FOP mice, with both populations exhibiting inflammatory and osteochondrogenic transcriptional signatures. Cell–cell interaction analysis revealed a self-reinforcing network of cytokine signaling among MPs and a prominent MP–FAP communication axis centred on SPP1. Functional studies confirmed that SPP1 enhanced FAP osteogenic differentiation and that its inhibition partially reversed this phenotype<i> in vitro</i> and attenuated HO in <i>vivo</i>. Our findings highlight the critical role of inflammatory MPs in shaping the fate of resident stromal mesenchymal progenitors (e.g. FAP) and suggest that early immune–stromal interactions set the stage for HO. Targeting this immune–mesenchymal crosstalk may represent a potential complementary strategy for preventing or mitigating disease progression in FOP.</p>

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Single-Cell dissection of fibrodysplasia ossificans progressiva identifies SPP1 as a mediator of macrophage–fibroadipogenic progenitors crosstalk

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Riccardo Gamberale,
  • Mauro Bergamaschi,
  • Anna Sofia Tascini,
  • Cristina D’Orlando,
  • Michela Signo,
  • Antonello Spinelli,
  • Raffaella Meneveri,
  • Renata Bocciardi,
  • Bénédicte Chazaud,
  • Emanuele Azzoni,
  • Silvia Brunelli

摘要

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder caused by gain-of-function mutations in ACVR1/ALK2, leading to progressive heterotopic ossification (HO) through endochondral bone formation. Inflammatory flare-ups often precede new ossification events, but the cellular and molecular mechanisms linking immune responses to progenitor cell fate remain incompletely understood. Here, using a tamoxifen-inducible Acvr1R206H mouse model of FOP and a reproducible muscle injury protocol, we combined single-cell RNA sequencing with in vitro assays to dissect early events during lesion formation. We identified an expansion of macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in FOP mice, with both populations exhibiting inflammatory and osteochondrogenic transcriptional signatures. Cell–cell interaction analysis revealed a self-reinforcing network of cytokine signaling among MPs and a prominent MP–FAP communication axis centred on SPP1. Functional studies confirmed that SPP1 enhanced FAP osteogenic differentiation and that its inhibition partially reversed this phenotype in vitro and attenuated HO in vivo. Our findings highlight the critical role of inflammatory MPs in shaping the fate of resident stromal mesenchymal progenitors (e.g. FAP) and suggest that early immune–stromal interactions set the stage for HO. Targeting this immune–mesenchymal crosstalk may represent a potential complementary strategy for preventing or mitigating disease progression in FOP.