Pluripotent Stem Cells Derived Mesenchymal Stromal Cells Improve Therapies for Advanced Cancers

Bone marrow Mesenchymal stromal cells (BM-MSCs) have a unique tumor-homing capacity and are a promising vehicle of gene therapy for advanced cancers. However, BM-MSCs are difficult to genetically engineer due to their limited expandability and may promote cancer progression. Large amount of MSC-like cells can be derived from embryonic stem cells (ESCs) or iPS cells, which will greatly facilitate engineering and expansion of MSCs carrying anti-cancer genes. Starting from a human iPS cell line CY2 free of reprogramming transgenes, we derived adherent cells expressing typical MSC surface markers (PSC-MSCs). These PSC-MSCs have the same karyotypes as the parental line and did not form teratoma in our initial studies, whereas the parent line did so robustly. Similar to BM-MSCs, these PSC-MSCs differentiated into bone and adipocytes in vitro, and showed homing property to cancer cells in vitro with comparable expression of genes related with tumor tropism. Notably, these PSC-MSCs express much low level of receptors for TGF-beta and Interleukin-1, two major cytokines inducing the pro-tumor activities of BM-MSCs. Consistently, after stimulation with TGF-beta, Interleukin-1 or tumor-conditioned medium, the expression of multiple pro-tumor factors was much lower in PSC-MSCs than that in BM-MSCs. Moreover, when co-cultured with various cancer cells, PSC-MSCs did not promote the epithelial-mesenchymal transition of cancer cells or expand the cancer stem cell population as BM-MSCs did. On the other hand, when stimulated with TNF-alpha and poly dA/dT, PSC-MSCs expressed high level of Trail and were capable to induce apoptosis of cancer cells in vitro. These data suggest that PSC-MSCs are a promising safer alternate of BM-MSCs with better expandability and genetic engineering potential.