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

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 tumorbearing 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/10 6 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.

Human Wharton’s Jelly Stem Cell Secretions Inhibit Human Leukemic Cell Line K562 in vitro by Inducing Cell Cycle Arrest and Apoptosis

“…However, the limitations observed with the widespread use of UCBT are in part due to their delay in the replenishment of the hematopoietic microenvironment and the immune competency to overcome the original disorder (Algeri et al, 2020). The MSCs, apart from their use as cell-based therapies in regenerative medicine, are reported to have both pro-or anti-cancer properties, either in their naïve state or after being engineered to carry apoptotic inducers or small molecules (Hmadcha et al, 2020;Wu et al, 2020).…”

Mesenchymal Stem Cells in Gastric Cancer: Vicious but Hopeful

“…As the stromal progenitor cells, their role in tumor progression and TME is being put under the spotlight of tumor researches. Most studies have confirmed the tumorcontributing role of MSC, while the anti-tumor effect of MSC gradually unveils in several cancer types such as melanoma; glioma; HCC (92)(93)(94). Also, there are opposite results clarifying that MSC from human adipose tissue and the umbilical cord could inhibit GC progression and induce apoptosis of cancer cells (95,96).…”

Comparative analysis of mesenchymal stem/stromal cells derived from human induced pluripotent stem cells and the cognate umbilical cord mesenchymal stem/stromal cells

“…To date, many studies have showed iMSCs presented traditional three-lineage differentiation capacity, including osteocytes, chondrocytes and adipocytes. For example, antibody-mediated osseous regeneration (AMOR) has been proved as a promising strategy for osteogenic differentiation of iMSCs [ 24 , 28 ]; Jungbluth et al, has indicated iMSCs combined with calcium phosphate granules (CPG) showed greater role in critical-size defects in the proximal tibias of mini-pigs in the early phase of bone healing compared to that of autologous bone marrow derived MSCs or CPG alone [ 29 ]. Holding the mesoblast lineage cell differentiation capacity of iMSCs is well described, but the ability of transdermal differentiation of iMSCs is still unexplored.…”