Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation
Abstract 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 an...
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Nature Portfolio
2025-06-01
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| Series: | npj Regenerative Medicine |
| Online Access: | https://doi.org/10.1038/s41536-025-00405-2 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zeji Du |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-3e2d92ed3adc4c03b1519de7bae537cd |
| institution | DOAJ |
| issn | 2057-3995 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Regenerative Medicine |
| spelling | doaj-art-3e2d92ed3adc4c03b1519de7bae537cd2025-08-20T03:10:38ZengNature Portfolionpj Regenerative Medicine2057-39952025-06-0110111610.1038/s41536-025-00405-2Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formationZeji Du0Skylar A. Rizzo1Tiffany L. Sarrafian2Monique S. Bagwell3Ryan C. Mahlberg4Ashley Amontree5Paige Schiebel6Dinah M. Tauferner7Zoe S. LeBrasseur8Tyra A. Witt9Mary Nagel10Kyla A. Boyd11Humberto De Vitto12Matthew L. Hillestad13Paul G. Stalboerger14Matthew T. Houdek15Rafael J. Sierra16Atta Behfar17Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineMayo Clinic Department of Virology and Gene Therapy, Mayo ClinicVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineMayo Clinic Department of Orthopedic MedicineMayo Clinic Department of Orthopedic MedicineVan Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative MedicineAbstract 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.https://doi.org/10.1038/s41536-025-00405-2 |
| spellingShingle | 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 Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation npj Regenerative Medicine |
| title | Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation |
| title_full | Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation |
| title_fullStr | Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation |
| title_full_unstemmed | Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation |
| title_short | Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation |
| title_sort | engineered bmp2 bmp7 extracellular vesicles induce autocrine bmp release driving smad phosphorylation to promote bone formation |
| url | https://doi.org/10.1038/s41536-025-00405-2 |
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