Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Nat Neurosci. 2011 Dec 25;15(2):197-204. doi: 10.1038/nn.3019.
Therapeutically engineered stem cells have shown promise for glioblastoma multiforme (GBM) therapy; however, key preclinical studies are urgently needed for their clinical translation. In this study, we investigated a new approach to GBM treatment using therapeutic stem cells encapsulated in biodegradable, synthetic extracellular matrix (sECM) in mouse models of human GBM resection. Using multimodal imaging, we first showed quantitative surgical debulking of human GBM tumors in mice, which resulted in increased survival. Next, sECM encapsulation of engineered stem cells increased their retention in the tumor resection cavity, permitted tumor-selective migration and release of diagnostic and therapeutic proteins in vivo. Simulating the clinical scenario of GBM treatment, the release of tumor-selective S-TRAIL (secretable tumor necrosis factor apoptosis inducing ligand) from sECM-encapsulated stem cells in the resection cavity eradicated residual tumor cells by inducing caspase-mediated apoptosis, delayed tumor regrowth and significantly increased survival of mice. This study demonstrates the efficacy of encapsulated therapeutic stem cells in mouse models of GBM resection and may have implications for developing effective therapies for GBM.
治疗性工程化干细胞在多形性胶质母细胞瘤（GBM）治疗中显示出前景；然而，它们的临床转化迫切需要进行关键的临床前研究。在这项研究中，我们使用可生物降解的合成细胞外基质（sECM）包封治疗性干细胞，在人类 GBM 切除的小鼠模型中研究了一种治疗 GBM 的新方法。使用多模态成像，我们首先在小鼠中显示了人类 GBM 肿瘤的定量手术减瘤，这导致了生存率的提高。接下来，工程化干细胞的 sECM 包封增加了它们在肿瘤切除腔中的保留，允许肿瘤选择性迁移，并在体内释放诊断和治疗蛋白。模拟 GBM 治疗的临床情况，sECM 包封的干细胞在切除腔中释放肿瘤选择性 S-TRAIL（可分泌肿瘤坏死因子凋亡诱导配体），通过诱导半胱天冬酶介导的细胞凋亡来根除残留的肿瘤细胞，延迟肿瘤复发，并显著提高小鼠的存活率。这项研究证明了包封治疗性干细胞在 GBM 切除的小鼠模型中的疗效，这可能对开发 GBM 的有效治疗方法具有重要意义。
