TGFB1-driven mesenchymal stem cell-mediated NIS gene transfer.

Area of Science:

• Biomedical Engineering
• Cancer Gene Therapy
• Stem Cell Biology

Background:

• Mesenchymal stem cells (MSCs) possess inherent tumor-homing capabilities, making them attractive for targeted gene delivery in cancer therapy.
• Genetically engineered MSCs expressing the sodium iodide symporter (NIS) enable noninvasive tracking and therapeutic applications using radioiodine.
• Tumor stroma-activated promoters can enhance the specificity of MSC-mediated transgene delivery.

Purpose of the Study:

• To develop and evaluate MSCs engineered to express NIS under the control of a SMAD-responsive promoter, activated by tumor microenvironment signals.
• To assess the tumor-specific homing and NIS expression of these engineered MSCs in a preclinical cancer model.
• To determine the therapeutic efficacy of 131I therapy delivered via these engineered MSCs.

Main Methods:

• Bone marrow-derived MSCs were stably transfected with a NIS-expressing plasmid driven by a synthetic SMAD-responsive promoter (SMAD-NIS-MSCs).
• Radioiodide uptake assays were performed to confirm NIS-mediated uptake after TGFB1 stimulation.
• 123I-scintigraphy was used to visualize tumor-specific radioiodide accumulation in vivo.
• Tumor growth and survival were monitored in mice treated with 131I-labeled SMAD-NIS-MSCs.

Main Results:

• SMAD-NIS-MSCs exhibited a significant 4.9-fold increase in NIS-mediated iodide uptake upon TGFB1 stimulation, confirming promoter responsiveness.
• 123I-scintigraphy demonstrated significant tumor-specific radioiodide accumulation in mice bearing TGFB1-expressing HuH7 hepatocellular carcinoma tumors.
• Treatment with 131I-labeled SMAD-NIS-MSCs resulted in a significant delay in tumor growth and prolonged survival in treated mice.

Conclusions:

• Engineered MSCs utilizing tumoral TGFB1 signaling via a SMAD-responsive promoter offer a promising strategy for tumor-selective NIS gene delivery.
• This approach enhances the specificity of NIS transgene expression in TGFB1-rich tumor environments.
• MSC-mediated NIS gene delivery holds potential for tailored, targeted radioiodine-based cancer gene therapy.