Loss of immunosuppressive and anti-inflammatory properties in transformed human mesenchymal stem cells

We used collection of sequentially mutated BM-hMSCs ranging from wild type (no oncogenic hits) to fully transformed hMSCs (targeted with up six oncogenic mutations)to address whether BM-hMSCs at different stages of a well-characterized oncogenic process (normal, immortalized, transformed) retain immunomodulatory properties in vitro and in vivo. We characterize, for the first time, an oncogenic transformation-associated loss of the immunesuppressive and anti-inflammatory properties by hMSCs and identify candidate immune effectors underlying the loss of immunomodulation in transformed hMSCs. Wild type BM-hMSCs (MSC-0H-GFP) did not develop tumors, meanwhile hMSCs transformed sequentially transformed with 5 oncogenic lesions (p53 inactivation; Rb inactivation; expression of hTERT; stabilization of c-myc; and expression of oncogenic H-RAS) (MSC-5H-GFP) cells gave rise to undifferentiated sarcomas when inoculated into immunedeficient mice. The tumoral transformation process causes the loss of the immunosuppressive and anti-inflamatory propierties of MSC-5H-GFP cells as compared to those of the wild type MSC-0H-GFP cells. To understand the basis of this loss of immunosuppression in transformed hMSCs, gene expression analysis was performed to create the list of differentially expressed genes between MSC-0H-GFP and MSC-5H-GFP cells. Further analysis of altered signaling pathways and upstream regulators were performed using the Ingenuity Pathway Analysis software.