Department of Orthopaedics, Xinqiao Hospital, Amy Medical University (Third Military Medical University), Chongqing, PR China.
Institute of Cancer, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, PR China.
Acta Biomater. 2020 May;108:223-236. doi: 10.1016/j.actbio.2020.03.010. Epub 2020 Mar 9.
The periosteum plays a critical role in bone formation and defect reconstruction. The concept of tissue engineering in the periosteum has been suggested to solve the clinical problems related to bone defect repair. Insertion of polymethyl methacrylate (PMMA) bone cement can induce the autologous generation of a tissue-engineered periosteum and has been considered as a promising strategy for bone defect reconstruction. The PMMA-induced membrane is a crucial element in the reconstruction of bone defects, especially for angiogenesis, but its biological mechanism remains elusive. Here, a PMMA-induced membrane model was established using a femoral critically sized defect in mice. We identified myeloid-derived suppressor cells (MDSCs) as a regulatory component of induced membrane vascularization. The increased number of MDSCs was markedly linked to increased membrane thickness and capillary density. Importantly, the results of an in vitro coculture assay indicated that MDSCs of the induced membrane further facilitated the angiogenic capacity of human umbilical vein endothelial cells (HUVECs) by upregulating the expression of VEGFA, Ang2 and HIF-1α. Furthermore, signaling pathway blockade results suggested that STAT3 activation is involved in the upregulation of VEGFA, Ang2 and HIF-1α expression in induced membrane MDSCs. Our findings provide new insights into the mechanism of angiogenesis in the PMMA-induced membrane and confirm the key signaling molecules of MDSCs in induced membrane angiogenesis. Based on these results, this strategy may become a new therapy for the treatment of large bone defects in the future. STATEMENT OF SIGNIFICANCE: In this study, we established an autologous tissue-engineered periosteum - PMMA-induced membrane, which was formed by the foreign body reaction to PMMA bone cement. The induced membrane establishes a blood supply for the large bone defect healing. After investigation, our study discovered the critical cell type in the formation and angiogenesis processes of the induced membrane, myeloid-derived suppressor cells (MDSCs). We revealed that MDSCs of the induced membrane promote the angiogenesis of endothelial cells through the expression of VEGFA, Ang2 and HIF-1α, which was upregulated by the activation of STAT3 signaling. Our findings clarified the beneficial effect of MDSCs in the angiogenesis of bone repair, and offered an additional target for the study of foreign body reactions to bone repair materials.
骨膜在骨形成和缺损重建中起着关键作用。骨膜组织工程的概念被提出，以解决与骨缺损修复相关的临床问题。聚甲基丙烯酸甲酯（PMMA）骨水泥的插入可以诱导自体组织工程骨膜的生成，被认为是骨缺损重建的一种有前途的策略。PMMA 诱导膜是骨缺损重建的关键因素，特别是在血管生成方面，但它的生物学机制仍不清楚。在这里，我们使用小鼠股骨临界缺损建立了 PMMA 诱导膜模型。我们确定髓系来源的抑制性细胞（MDSCs）是诱导膜血管生成的调节成分。MDSCs 的数量增加与膜厚度和毛细血管密度的增加明显相关。重要的是，体外共培养实验结果表明，诱导膜中的 MDSCs 通过上调 VEGFA、Ang2 和 HIF-1α 的表达，进一步促进人脐静脉内皮细胞（HUVECs）的血管生成能力。此外，信号通路阻断结果表明，STAT3 激活参与诱导膜 MDSCs 中 VEGFA、Ang2 和 HIF-1α 表达的上调。我们的研究结果为 PMMA 诱导膜血管生成的机制提供了新的见解，并证实了 MDSCs 在诱导膜血管生成中的关键信号分子。基于这些结果，该策略可能成为未来治疗大骨缺损的一种新疗法。
在这项研究中，我们建立了一种自体组织工程化的骨膜 - PMMA 诱导膜，它是由 PMMA 骨水泥的异物反应形成的。诱导膜为大骨缺损的愈合建立了血液供应。经过研究，我们发现了诱导膜形成和血管生成过程中的关键细胞类型，即髓系来源的抑制性细胞（MDSCs）。我们揭示了诱导膜中的 MDSCs 通过激活 STAT3 信号通路上调 VEGFA、Ang2 和 HIF-1α 的表达，促进内皮细胞的血管生成。我们的研究结果阐明了 MDSCs 在骨修复血管生成中的有益作用，并为骨修复材料异物反应的研究提供了另一个靶点。
