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

IF 6.5 1区 医学 Q1 CELL & TISSUE ENGINEERING
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
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引用次数: 0

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.

工程化的BMP2/BMP7细胞外囊泡诱导自分泌BMP释放,驱动SMAD磷酸化,促进骨形成。
在美国,骨愈合受损每年影响约60万患者。骨形态发生蛋白2 (rhBMP2)的治疗受到低骨质量和不良反应的阻碍。在这里,间充质干细胞被改造成产生含有细胞外囊泡的BMP2和BMP2/7 (BMP2- ev和BMP2/7- ev),提供了一种刺激骨形成的替代方法。BMP2-EV和BMP2/7-EV驱动钙沉积和碱性磷酸酶活性增加;骨组织、RUNX2、骨钙素和骨桥蛋白的增加证明了成骨细胞的分化。BMP2/7-EV诱导的SMAD磷酸化和钙沉积被BMP I受体抑制剂DMH1抑制,显示出BMP受体依赖性。BMP拮抗剂Noggin治疗后,证实BMP2和BMP7细胞外囊泡包封保持效力。BMP2/7-EV在大鼠颅骨缺损模型中的应用在显微计算机断层扫描和组织病理学分析中显示骨形成增强,与rhBMP2相当。BMP2/7-EV介导的骨形成强调了ev作为一种独特的多价再生生物疗法的递送方式。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
npj Regenerative Medicine
npj Regenerative Medicine Engineering-Biomedical Engineering
CiteScore
10.00
自引率
1.40%
发文量
71
审稿时长
12 weeks
期刊介绍: Regenerative Medicine, an innovative online-only journal, aims to advance research in the field of repairing and regenerating damaged tissues and organs within the human body. As a part of the prestigious Nature Partner Journals series and in partnership with ARMI, this high-quality, open access journal serves as a platform for scientists to explore effective therapies that harness the body's natural regenerative capabilities. With a focus on understanding the fundamental mechanisms of tissue damage and regeneration, npj Regenerative Medicine actively encourages studies that bridge the gap between basic research and clinical tissue repair strategies.
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