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<p>In the United States, impaired bone healing impacts ~600,000 patients annually. Bone morphogenetic protein 2 (rhBMP2) therapy is impeded by low bone quality and adverse effects. Here, mesenchymal stem cells, engineered to produce BMP2 and BMP2/7 containing extracellular vesicles (BMP2-EV and BMP2/7-EV), provided an alternative means of stimulating bone formation. BMP2-EV and BMP2/7-EV drove increased calcium deposition and alkaline phosphatase activity; with increase in osterix, RUNX2, osteocalcin, and osteopontin documenting osteoblast differentiation. BMP2/7-EV induced SMAD phosphorylation and calcium deposition, was inhibited by DMH1, a BMP I receptor inhibitor, demonstrating BMP receptor dependence. BMP2 and BMP7 extracellular vesicle encapsulation was confirmed with preserved potency following treatment with BMP antagonist, Noggin. Application of BMP2/7-EV in a rat calvarial defect model demonstrated enhanced bone formation on micro-computed tomography and histopathologic analysis, equaling rhBMP2. BMP2/7-EV mediated bone formation here highlights EVs as a unique modality for delivery of tailored polyvalent regenerative biotherapies.</p><p></p>

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Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月3日

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  • Zeji Du,
  • Skylar A. Rizzo,
  • Tiffany L. Sarrafian,
  • Monique S. Bagwell,
  • Ryan C. Mahlberg,
  • Ashley Amontree,
  • Paige Schiebel,
  • Dinah M. Tauferner,
  • Zoe S. LeBrasseur,
  • Tyra A. Witt,
  • Mary Nagel,
  • Kyla A. Boyd,
  • Humberto De Vitto,
  • Matthew L. Hillestad,
  • Paul G. Stalboerger,
  • Matthew T. Houdek,
  • Rafael J. Sierra,
  • Atta Behfar

摘要

In the United States, impaired bone healing impacts ~600,000 patients annually. Bone morphogenetic protein 2 (rhBMP2) therapy is impeded by low bone quality and adverse effects. Here, mesenchymal stem cells, engineered to produce BMP2 and BMP2/7 containing extracellular vesicles (BMP2-EV and BMP2/7-EV), provided an alternative means of stimulating bone formation. BMP2-EV and BMP2/7-EV drove increased calcium deposition and alkaline phosphatase activity; with increase in osterix, RUNX2, osteocalcin, and osteopontin documenting osteoblast differentiation. BMP2/7-EV induced SMAD phosphorylation and calcium deposition, was inhibited by DMH1, a BMP I receptor inhibitor, demonstrating BMP receptor dependence. BMP2 and BMP7 extracellular vesicle encapsulation was confirmed with preserved potency following treatment with BMP antagonist, Noggin. Application of BMP2/7-EV in a rat calvarial defect model demonstrated enhanced bone formation on micro-computed tomography and histopathologic analysis, equaling rhBMP2. BMP2/7-EV mediated bone formation here highlights EVs as a unique modality for delivery of tailored polyvalent regenerative biotherapies.