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<p>Fibro-Adipogenic Progenitors (FAPs) are muscle-resident mesenchymal stromal cells that are essential for skeletal muscle regeneration, but also drive pathological fibrosis and adiposity. FAP properties have been modulated by transgenic strategies, but the field lacks an efficient tool for specific, localized, in vivo FAP targeting. Adeno-Associated Viruses (AAVs) have become a standard for delivery of transgenes with both natural and engineered cell specificity for uptake, or tropism. The goal of this study was to develop an AAV system with FAP specificity. We isolated the promoter for murine platelet derived growth factor receptor alpha (<i>Pdgfra</i>), a FAP-specific marker, to drive expression of the reporter, ZsGreen. Cell transfection confirmed that full-length (2.2&#xa0;kb) and truncated (826&#xa0;bp) promoters restricted expression to FAPs, with the 826&#xa0;bp sequence providing higher gene expression. Next, we compared AAV5 and AAV8 serotypes, packaging each promoter sequence versus the CMV promoter or to no vector. Following intramuscular AAV injection (1 × 10<sup>11</sup>vg/TA), immunofluorescence and cell-sorting revealed that AAV5 harboring the 826&#xa0;bp <i>Pdgfra</i> promoter provided optimal FAP specificity and expression level. Importantly, minimal off-target expression in myofibers or other mononucleated populations, including endothelial, immune, and satellite cells was found. These results demonstrate the development of an AAV-based tool for precise, in vivo manipulation of FAPs.</p>

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Selective targeting of skeletal muscle resident fibro-adipogenic progenitors via recombinant adeno-associated viral delivery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月12日

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  • Yangyi E. Luo,
  • Elisabeth R. Barton

摘要

Fibro-Adipogenic Progenitors (FAPs) are muscle-resident mesenchymal stromal cells that are essential for skeletal muscle regeneration, but also drive pathological fibrosis and adiposity. FAP properties have been modulated by transgenic strategies, but the field lacks an efficient tool for specific, localized, in vivo FAP targeting. Adeno-Associated Viruses (AAVs) have become a standard for delivery of transgenes with both natural and engineered cell specificity for uptake, or tropism. The goal of this study was to develop an AAV system with FAP specificity. We isolated the promoter for murine platelet derived growth factor receptor alpha (Pdgfra), a FAP-specific marker, to drive expression of the reporter, ZsGreen. Cell transfection confirmed that full-length (2.2 kb) and truncated (826 bp) promoters restricted expression to FAPs, with the 826 bp sequence providing higher gene expression. Next, we compared AAV5 and AAV8 serotypes, packaging each promoter sequence versus the CMV promoter or to no vector. Following intramuscular AAV injection (1 × 1011vg/TA), immunofluorescence and cell-sorting revealed that AAV5 harboring the 826 bp Pdgfra promoter provided optimal FAP specificity and expression level. Importantly, minimal off-target expression in myofibers or other mononucleated populations, including endothelial, immune, and satellite cells was found. These results demonstrate the development of an AAV-based tool for precise, in vivo manipulation of FAPs.