Mesenchymal stem cells derived from iPSCs expressing interleukin-24 inhibit the growth of melanoma in the tumor-bearing mouse model

Zheng Wu; Wei Liu; Zujia Wang; Baitao Zeng; Guangnan Peng; Hongyan Niu; Linlin Chen; Cong Liu; Qian Hu; Yuxuan Zhang; Mengmeng Pan; Lingqian Wu; Mujun Liu; Xionghao Liu; Desheng Liang

doi:10.1186/s12935-020-1112-7

Mesenchymal stem cells derived from iPSCs expressing interleukin-24 inhibit the growth of melanoma in the tumor-bearing mouse model

Cancer Cell Int. 2020 Jan 30:20:33. doi: 10.1186/s12935-020-1112-7. eCollection 2020.

Authors

Zheng Wu^#¹, Wei Liu^#¹, Zujia Wang¹, Baitao Zeng¹, Guangnan Peng¹, Hongyan Niu¹, Linlin Chen¹, Cong Liu¹, Qian Hu¹, Yuxuan Zhang¹, Mengmeng Pan¹, Lingqian Wu^{1

2}, Mujun Liu^{3

2}, Xionghao Liu^{1

2}, Desheng Liang^{1

2}

Affiliations

¹ 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.
² 3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China.
³ 2Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan China.

^# Contributed equally.

Abstract

Background: Interleukin-24 (IL-24) is a therapeutic gene for melanoma, which can induce melanoma cell apoptosis. Mesenchymal stem cells (MSCs) show promise as a carrier to delivery anti-cancer factors to tumor tissues. Induced pluripotent stem cells (iPSCs) are an alternative source of mesenchymal stem cells (MSCs). We previously developed a novel non-viral gene targeting vector to target IL-24 to human iPSCs. This study aims to investigate whether MSCs derived from the iPSCs with the site-specific integration of IL-24 can inhibit the growth of melanoma in a tumor-bearing mouse model via retro-orbital injection.

Methods: IL-24-iPSCs were differentiated into IL-24-iMSCs in vitro, of which cellular properties and potential of differentiation were characterized. The expression of IL-24 in the IL-24-iMSCs was measured by qRT-PCR, Western Blotting, and ELISA analysis. IL-24-iMSCs were transplanted into the melanoma-bearing mice by retro-orbital intravenous injection. The inhibitory effect of IL-24-iMSCs on the melanoma cells was investigated in a co-culture system and tumor-bearing mice. The molecular mechanisms underlying IL-24-iMSCs in exerting anti-tumor effect were also explored.

Results: iPSCs-derived iMSCs have the typical profile of cell surface markers of MSCs and have the ability to differentiate into osteoblasts, adipocytes, and chondroblasts. The expression level of IL-24 in IL-24-iMSCs reached 95.39 ng/10⁶ cells/24 h, which is significantly higher than that in iMSCs, inducing melanoma cells apoptosis more effectively in vitro compared with iMSCs. IL-24-iMSCs exerted a significant inhibitory effect on the growth of melanoma in subcutaneous mouse models, in which the migration of IL-24-iMSCs to tumor tissue was confirmed. Additionally, increased expression of Bax and Cleaved caspase-3 and down-regulation of Bcl-2 were observed in the mice treated with IL-24-iMSCs.

Conclusion: MSCs derived from iPSCs with the integration of IL-24 at rDNA locus can inhibit the growth of melanoma in tumor-bearing mouse models when administrated via retro-orbital injection.

Keywords: Human rDNA locus; Interleukin-24; Melanoma; Site-specific Integration; iPSCs-derived MSCs.