Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4.
Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4.
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DOI：
10.1172/jci15153
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发表时间：
2002-09
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影响因子：
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通讯作者：
Hairong Peng;V. Wright;A. Usas;B. Gearhart;H. Shen;J. Cummins;J. Huard
中科院分区：
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作者：
Hairong Peng;V. Wright;A. Usas;B. Gearhart;H. Shen;J. Cummins;J. Huard
我们研究了血管生成和成骨因子在骨形成和骨愈合中的相互作用，使用基因工程表达人骨形态发生蛋白4（BMP 4）、VEGF或VEGF特异性拮抗剂（可溶性Flt1）的肌源性干细胞进行离体基因治疗。我们的研究结果表明，虽然VEGF单独没有改善骨再生，它与BMP 4协同作用，以增加间充质干细胞的招募，提高细胞存活率，并增加软骨内骨形成的早期阶段的软骨形成。这些早期效应，加上加速的软骨吸收，最终导致骨形成和骨愈合的显著增强。VEGF对由BMP 4引起的骨愈合的有益作用关键取决于VEGF与BMP 4的比率，不适当的比率导致对骨愈合的有害作用。最后，我们表明，可溶性Flt1抑制骨形成引起的BMP 4。因此，VEGF在BMP 4诱导的骨形成中起重要作用，并且它可以通过多种机制显著增强BMP 4诱导的骨形成和再生。这项研究对制定新的策略具有重要意义，通过增加间充质干细胞的招募和存活，结合基于肌肉来源的干细胞的基因治疗来改善骨愈合。
We investigated the interaction between angiogenic and osteogenic factors in bone formation and bone healing with ex vivo gene therapy using muscle-derived stem cells genetically engineered to express human bone morphogenetic protein-4 (BMP4), VEGF, or VEGF-specific antagonist (soluble Flt1). Our results show that although VEGF alone did not improve bone regeneration, it acted synergistically with BMP4 to increase recruitment of mesenchymal stem cells, to enhance cell survival, and to augment cartilage formation in the early stages of endochondral bone formation. These early effects, coupled with accelerated cartilage resorption, eventually led to a significant enhancement of bone formation and bone healing. The beneficial effect of VEGF on bone healing elicited by BMP4 depends critically on the ratio of VEGF to BMP4, with an improper ratio leading to detrimental effects on bone healing. Finally, we show that soluble Flt1 inhibits bone formation elicited by BMP4. Thus, VEGF plays an important role in bone formation elicited by BMP4, and it can significantly enhance BMP4-elicited bone formation and regeneration through multiple mechanisms. This study has important implications for the formulation of new strategies to improve bone healing through increasing mesenchymal stem cell recruitment and survival, in combination with muscle-derived stem cell-based gene therapy.