Therapeutic efficacy and safety of TRAIL-producing human adipose tissue-derived mesenchymal stem cells against experimental brainstem glioma

Abstract

Mesenchymal stem cells (MSCs) have an extensive migratory capacity for gliomas, which is comparable to that of neural stem cells. Among the various types of MSCs, human adipose tissue-derived MSCs (hAT-MSC) emerge as one of the most attractive vehicles for gene therapy because of their high throughput, lack of ethical concerns, and availability and ease of isolation. We evaluated the therapeutic potential and safety of genetically engineered hAT-MSCs encoding the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against brainstem gliomas. Human AT-MSCs were isolated from human fat tissue, characterized, and transfected with TRAIL using nucleofector. The therapeutic potential of TRAIL-producing hAT-MSCs (hAT-MSC.TRAIL) was confirmed using in vitro and in vivo studies. The final fate of injected hAT-MSCs was traced in long-survival animals. The characterization of hAT-MSCs revealed the expression of MSC-specific cell-type markers and their differentiation potential into mesenchymal lineage. Short-term outcomes included a 56.3% reduction of tumor volume (P < .001) with increased apoptosis (3.03-fold, P < .05) in animals treated with hAT-MSC.TRAIL compared with the control groups. Long-term outcomes included a significant survival benefit in the hAT-MSC.TRAIL-treated group (26 days of median survival in the control group vs 84 days in the hAT-MSC.TRAIL-treated group, P < .0001), without any evidence of mesenchymal differentiation in vivo. Our study demonstrated the therapeutic efficacy and safety of nonvirally engineered hAT-MSCs against brainstem gliomas and showed the possibility of stem-cell-based targeted gene therapy for clinical application.

Therapeutic strategies targeting cancer stem cells

“…MiR-34 restoration also significantly inhibites the self-renewal at the site of tumors. 75 It has been shown that TRAIL-expressing MSCs can significantly inhibit tumor growth and induce significant survival benefits in animal models; 76,77 moreover, MSCs expressing TRAIL can cause apoptosis or death and reduce colony formation of SP cells in quamous (H357) and lung (A549) cancer cell lines and act in synergy with conventional chemotherapy. 78 The sensitivity of cancer stem-like cells to TRAIL is various may be due to their different genetic background.…”

The inhibitory effect of MSCs expressing TRAIL as a cellular delivery vehicle in combination with cisplatin on hepatocellular carcinoma

“…[29][30][31] MSCs expressing TRAIL exhibited short-and long-term therapeutic effects without significant complications in glioma. [32][33][34][35] But there was no report about TRAIL gene modified MSCs (TRAIL-MSCs) in the therapy of HCC. As mentioned above, HCC cells showed high resistance to TRAIL, so TRAIL-MSCs alone might be difficult to achieve desired effect.…”

Mesenchymal stem cells as therapeutic agents and in gene delivery for the treatment of glioma

“…These factors make TRAIL an attractive genetic tool for use in the treatment of tumors. Choi et al (2011) were the first to demonstrate short-and long-term therapeutic efficacies using TRAIL-producing human AT-MSCs. Their study included both in vitro and in vivo experiments.…”