背景:损伤后淋巴系统的功能障碍,疾病,或者癌症治疗会导致淋巴水肿,无法治愈的衰弱状况。尽管有各种物理治疗和手术选择,大多数治疗都是姑息性的,不能解决潜在的淋巴管功能不全导致淋巴水肿进展的问题.干细胞疗法为治疗各种慢性疾病提供了有希望的替代方案,具有广泛的治疗效果,可以减少炎症,纤维化,和氧化应激,同时促进淋巴管(LV)再生。具体来说,建议干细胞移植促进LV恢复,重建淋巴循环,因此有可能被用于有效的淋巴水肿治疗。除了干细胞,有研究提出了血管内皮生长因子C(VEGFC)的给药,以促进淋巴管生成和减少淋巴水肿的肿胀。
目标:这里,我们寻求结合干细胞治疗的好处,它提供了一种可以对组织环境做出反应的细胞治疗方法,和VEGFC给药以恢复淋巴引流。
方法:具体来说,我们使用慢病毒载体(hVEGFCMSC)工程化间充质干细胞(MSC)过表达VEGFC,并使用近红外(NIR)成像研究其改善LV功能和组织肿胀的治疗功效。和单个LV结扎小鼠尾部淋巴水肿模型中的淋巴再生。
结果:首先,我们表明,使用慢病毒转导的VEGFC的过表达导致体外VEGFC蛋白合成增加。然后,我们证明了伤后hVEGFCMSC给药显著增加了淋巴收缩频率14-,21-,和术后28天,与体内对照动物(MSC给药)相比,与对照组相比,同时也减少了手术后28天的尾部肿胀。
结论:我们的结果表明,hVEGFCMSC在减轻继发性损伤后淋巴水肿进展过程中观察到的淋巴功能障碍方面具有治疗潜力,并且可以为增强自体细胞疗法治疗淋巴水肿提供有希望的方法。
Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Despite the various physical therapy and surgical options available, most treatments are palliative and fail to address the underlying lymphatic vascular insufficiency driving lymphedema progression. Stem cell therapy provides a promising alternative in the treatment of various chronic diseases with a wide range of therapeutic effects that reduce inflammation, fibrosis, and oxidative stress, while promoting lymphatic vessel (LV) regeneration. Specifically, stem cell transplantation is suggested to promote LV restoration, rebuild lymphatic circulation, and thus potentially be utilized towards an effective lymphedema treatment. In addition to stem cells, studies have proposed the administration of vascular endothelial growth factor C (VEGFC) to promote lymphangiogenesis and decrease swelling in lymphedema.
Here, we seek to combine the benefits of stem cell therapy, which provides a cellular therapeutic approach that can respond to the tissue environment, and VEGFC administration to restore lymphatic drainage.
Specifically, we engineered mesenchymal stem cells (MSCs) to overexpress VEGFC using a lentiviral vector (hVEGFC MSC) and investigated their therapeutic efficacy in improving LV function and tissue swelling using near infrared (NIR) imaging, and lymphatic regeneration in a single LV ligation mouse tail lymphedema model.
First, we showed that overexpression of VEGFC using lentiviral transduction led to an increase in VEGFC protein synthesis in vitro. Then, we demonstrated hVEGFC MSC administration post-injury significantly increased the lymphatic contraction frequency 14-, 21-, and 28-days post-surgery compared to the control animals (MSC administration) in vivo, while also reducing tail swelling 28-days post-surgery compared to controls.
Our results suggest a therapeutic potential of hVEGFC MSC in alleviating the lymphatic dysfunction observed during lymphedema progression after secondary injury and could provide a promising approach to enhancing autologous cell therapy for treating lymphedema.