Department of Gynecology and Obstetrics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China; Laboratory Animal Center, Nantong University, Nantong 226001, Jiangsu, China.
Department of Ophthalmology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China.
Int Immunopharmacol. 2023 May;118:110025. doi: 10.1016/j.intimp.2023.110025. Epub 2023 Mar 16.
The present study investigated whether bone marrow-derived mesenchymal stem cells (BMMSCs) facilitate angiogenesis and improve outcomes of pregnancy with obstetric deep venous thrombosis (DVT) and explored the underlying mechanism. A pregnant DVT rat model was established using a "stenosis" method on the lower segment of the inferior vena cava (IVC). The extent of vascularization in thrombosed IVC was examined by immunohistochemistry. In addition, the effect of BMMSCs on DVT pregnancy outcomes was evaluated. We also characterized the effect of BMMSC-derived conditioned medium (BM-CM) on the impaired human umbilical vein endothelial cells (HUVECs). Thereafter, transcriptome sequencing was employed to identify the differentially expressed genes in thrombosed IVC tissues of DVT and DVT plus BMMSCs (thrice) groups. Lastly, the candidate gene's role in the promotion of angiogenesis was demonstrated in vitro and in vivo. The DVT model was successfully established using IVC stenosis. The injection of three consecutive BMMSC doses into pregnant SD rats with DVT was demonstrated to be the most effective treatment, which significantly reduced the length and weight of the thrombus, induced the highest level of angiogenesis, and ameliorated the embryo absorption rate. In vitro, BM-CM efficiently increased the abilities of impaired endothelial cells to proliferate, migrate, invade, and form vessel-like tubes, while inhibiting their apoptosis. Transcriptome sequencing revealed that BMMSCs induced a prominent upregulation of a variety of pro-angiogenic genes, including secretogranin II (SCG2). When SCG2 expression was knocked down by lentivirus, the BMMSCs' and BM-CM-induced pro-angiogenic effects on pregnant DVT rats and HUVECs were markedly attenuated. In conclusion, the study results suggest that BMMSCs enhance angiogenesis via up-regulation of SCG2, providing an effective alternative regenerative agent and novel target for the therapy of obstetric DVT.
本研究旨在探讨骨髓间充质干细胞（BMMSCs）是否能促进血管生成，改善产科深静脉血栓形成（DVT）孕妇的妊娠结局，并探讨其潜在机制。采用下腔静脉（IVC）下段狭窄法建立妊娠 DVT 大鼠模型。通过免疫组织化学法检测血栓形成 IVC 的血管生成程度。此外，还评估了 BMMSCs 对 DVT 妊娠结局的影响。我们还研究了 BMMSC 衍生条件培养基（BM-CM）对受损人脐静脉内皮细胞（HUVECs）的影响。随后，采用转录组测序技术鉴定 DVT 组和 DVT+BMMSCs（三次）组血栓形成 IVC 组织中的差异表达基因。最后，在体外和体内验证候选基因在促进血管生成中的作用。采用 IVC 狭窄法成功建立了 DVT 模型。研究表明，向妊娠合并 DVT 的 SD 大鼠连续三次注射 BMMSC 是最有效的治疗方法，可显著降低血栓长度和重量，诱导最高水平的血管生成，并改善胚胎吸收率。体外实验结果表明，BM-CM 可有效增强受损内皮细胞的增殖、迁移、侵袭和形成管状血管的能力，同时抑制其凋亡。转录组测序结果显示，BMMSCs 可显著上调多种促血管生成基因，包括分泌颗粒蛋白 II（SCG2）。当 SCG2 表达被慢病毒敲低时，BMMSCs 及其 BM-CM 对妊娠合并 DVT 大鼠和 HUVECs 的促血管生成作用明显减弱。综上所述，该研究结果表明，BMMSCs 通过上调 SCG2 增强血管生成，为产科 DVT 的治疗提供了一种有效的再生治疗剂和新靶点。
