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一种由骨髓间充质干细胞、骨形态发生蛋白 9 （BMP9）基因慢病毒载体和 P3HB4HB 温敏水凝胶组成的复合组织工程骨材料（BMSCs-LV-BMP9-P3HB4HB）通过表达成骨因子修复大鼠颅骨缺损。

A Composite Tissue Engineered Bone Material Consisting of Bone Mesenchymal Stem Cells, Bone Morphogenetic Protein 9 (BMP9) Gene Lentiviral Vector, and P3HB4HB Thermogel (BMSCs-LV-BMP9-P3HB4HB) Repairs Calvarial Skull Defects in Rats by Expression of Osteogenic Factors.

机构信息

Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).

Department of Orthopedics, Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang, China (mainland).

出版信息

Med Sci Monit. 2020 Sep 7;26:e924666. doi: 10.12659/MSM.924666.

DOI:10.12659/MSM.924666
PMID:32894745
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7496453/
Abstract

BACKGROUND Bone tissue engineering has been proven to be an appropriate approach for treating bone defects. This study aimed to investigate the effects and mechanism of a composite tissue engineered bone material consisting of bone mesenchymal stem cells (BMSCs), bone morphogenetic protein (BMP9) gene lentiviral vector, and P3HB4HB thermogel (BMSCs-LV-BMP9-P3HB4HB) on calvarial skull defects in rats. MATERIAL AND METHODS LV-BMP9 viral vector was structured and infected to BMSCs-P3HB4HB composite scaffold, which was named as BMSCs-P3HB4HB composite bone repair material. Adipogenic differentiation was determined by oil-red O (ORO) and alkaline phosphatase (ALP) staining. Osteogenic differentiation was measured using Alizarin red staining. Cell viability was examined using Cell-Counting Kit-8 (CCK-8) assay. Protein expression of osteogenic factors, including BMP9, runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN), and osterix (OSX), was detected with Western blot assay and immunohistochemistry. mRNA of these osteogenic factors was examined by RT-PCR. Histological changes were examined with hematoxylin and eosin (H&E) and Masson's trichrome staining. Bone repair was measured using micro-computed tomography (micro-CT). RESULTS BMSCs and LV-BMP9-infected BMSCs demonstrated adipogenic and osteogenic differentiation potential. BMSCs-P3HB4HB scaffold demonstrated good cell-tissue compatibility. BMSCs-LV-BMP9-P3HB4HB exhibited significantly higher osteogenic ability and cell viability of BMSCs compared to BMSCs-LV-P3HB4HB (p<0.05). BMSCs-LV-BMP9-P3HB4HB significantly promoted osteogenic factors (RUNX2, OCN, OPN, and OSX) expression compared to the BMSCs-LV-P3HB4HB group (p<0.05) in both BMSCs and in calvarial defect rats. BMSCs-LV-BMP9-P3HB4HB demonstrated stronger repair ability. BMSCs-LV-BMP9-P3HB4HB significantly alleviated pathological injury and increased collagen fiber production compared to the BMSCs-LV-P3HB4HB group (p<0.05). CONCLUSIONS BMSCs-LV-BMP9-P3HB4HB composite bone repair material can effectively repair injured skull tissues of calvarial defect rats through triggering osteogenic factors expression. The present generated bone repair material may have applications in tissue engineering in regeneration of bone defects.

摘要

背景

骨组织工程已被证明是治疗骨缺损的一种合适方法。本研究旨在探讨由骨髓间充质干细胞（BMSCs）、骨形态发生蛋白 9 基因慢病毒载体和 P3HB4HB 温敏水凝胶组成的复合组织工程骨材料（BMSCs-LV-BMP9-P3HB4HB）对大鼠颅骨缺损的作用和机制。

材料和方法

构建 LV-BMP9 病毒载体并感染 BMSCs-P3HB4HB 复合支架，命名为 BMSCs-P3HB4HB 复合骨修复材料。油红 O（ORO）和碱性磷酸酶（ALP）染色检测成脂分化。茜素红染色检测成骨分化。细胞增殖实验（CCK-8）检测细胞活力。Western blot 和免疫组化检测成骨因子 BMP9、成骨相关转录因子 2（RUNX2）、骨钙素（OCN）、骨桥蛋白（OPN）和骨形成蛋白 4（OSX）的蛋白表达。RT-PCR 检测这些成骨因子的 mRNA 表达。苏木精和伊红（H&E）及 Masson 三色染色观察组织学变化。微计算机断层扫描（micro-CT）测量骨修复情况。

结果

BMSCs 和 LV-BMP9 感染的 BMSCs 表现出成脂和成骨分化潜能。BMSCs-P3HB4HB 支架具有良好的细胞组织相容性。与 BMSCs-LV-P3HB4HB 相比，BMSCs-LV-BMP9-P3HB4HB 组的 BMSCs 具有更高的成骨能力和细胞活力（p<0.05）。BMSCs-LV-BMP9-P3HB4HB 组在 BMSCs 和颅骨缺损大鼠中均显著促进成骨因子（RUNX2、OCN、OPN 和 OSX）的表达（p<0.05）。BMSCs-LV-BMP9-P3HB4HB 具有更强的修复能力。与 BMSCs-LV-P3HB4HB 组相比，BMSCs-LV-BMP9-P3HB4HB 组减轻了病理性损伤，增加了胶原纤维的产生（p<0.05）。

结论

BMSCs-LV-BMP9-P3HB4HB 复合骨修复材料可通过触发成骨因子表达有效修复颅骨缺损大鼠受损的组织。该新型骨修复材料有望应用于组织工程中骨缺损的再生。

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