Advances in the Masquelet technique: Myeloid-derived suppressor cells promote angiogenesis in PMMA-induced membranes
Advances in the Masquelet technique: Myeloid-derived suppressor cells promote angiogenesis in PMMA-induced membranes
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Masquelet技术的进展：骨髓源性抑制细胞促进PMMA诱导膜中的血管生成
DOI：
10.1016/j.actbio.2020.03.010
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发表时间：
2020-05-01
影响因子：
9.7
通讯作者：
Li, Jie
中科院分区：
文献类型：
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作者：
Wang, Wenkai;Zuo, Rui;Li, Jie
骨膜在骨形成和骨缺损重建中起着关键作用。骨膜组织工程的概念已被提出来解决骨缺损修复的相关临床问题。植入聚甲基丙烯酸甲酯（PMMA）骨水泥可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诱导的膜是骨缺损重建的关键因素，特别是对于血管生成，但其生物学机制仍不清楚。在此，使用小鼠股骨临界尺寸缺损建立PMMA诱导的膜模型。我们确定了髓源性抑制细胞（MDSC）作为诱导膜血管化的调节成分。MDSC数量的增加与膜厚度和毛细血管密度的增加显著相关。重要的是，体外共培养试验的结果表明，诱导膜的MDSC通过上调VEGFA、Ang 2和HIF-1 α的表达进一步促进了人脐静脉内皮细胞（HUVECs）的血管生成能力。此外，信号通路阻断结果表明，STAT 3激活参与了诱导的膜MDSC中VEGFA、Ang 2和HIF-1 α表达的上调。我们的研究结果提供了新的见解，在PMMA诱导的膜血管生成的机制，并确认在诱导膜血管生成的MDSC的关键信号分子。基于这些结果，这一策略可能成为一种新的治疗方法为大骨缺损的未来。声明的意义在本研究中，我们建立了自体组织工程骨膜-PMMA诱导膜，这是由异物反应PMMA骨水泥形成的。诱导膜为大骨缺损愈合建立血液供应。经过研究，本研究发现了诱导膜源性抑制细胞（MDSCs）形成和血管生成过程中的关键细胞类型。我们发现，诱导膜的MDSCs通过表达VEGFA、Ang 2和HIF-1 α促进内皮细胞的血管生成，而HIF-1 α的表达通过激活STAT 3信号而上调。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，并为骨修复材料的异物反应研究提供了另一个靶点。(C)2020 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
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-1 alpha. Furthermore, signaling pathway blockade results suggested that STAT3 activation is involved in the upregulation of VEGFA, Ang2 and HIF-1 alpha 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 SignificanceIn 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-1 alpha, 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. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.