Human Bone Marrow Stromal Cells Lose Immunosuppressive and Anti-inflammatory Properties upon Oncogenic Transformation

Summary

Because of their immunomodulatory properties, human bone marrow stromal cells (hBMSCs) represent promising stem cells for treatment of immune disorders. hBMSCs expansion precedes their clinical use, so the possibility that hBMSCs undergo spontaneous transformation upon long-term culture should be addressed. Whether hBMSCs retain immunosuppressive and anti-inflammatory properties upon oncogenic transformation remains unknown. Using sequentially mutated hBMSCs and spontaneously transformed hBMSCs, we report that, upon oncogenic transformation, hBMSCs lose immunosuppressive and anti-inflammatory properties in vitro and in vivo. Transcriptome profiling and functional assays reveal immune effectors underlying the loss of immunomodulation in transformed hBMSCs. They display a proinflammatory transcriptomic signature, with deregulation of immune and inflammatory modulators and regulators of the prostaglandin synthesis. Transformed hBMSCs lose their capacity to secrete the immunosuppressive prostacyclins prostaglandin E2 (PGE2) and PGI2 but produce proinflammatory thromboxanes. Together, the immunoregulatory profile adopted by hBMSCs largely depends on intrinsic genetic-molecular determinants triggered by genomic instability/oncogenic transformation.

Highlights

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  Oncogenic hBMSCs display robustly impaired immune properties

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  Transformed hBMSCs display a proinflammatory transcriptomic signature

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  Transformed hBMSCs lose capacity to secrete immunosuppressive prostacyclins

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  Transformed hBMSCs gain the capacity to produce proinflammatory thromboxanes

Abstract

In this study, Menendez, Delgado, and colleagues demonstrate that human bone marrow stromal/mesenchymal stem cells lose their immune properties in vitro and in vivo upon oncogenic transformation by skewing its anti-inflammatory phenotype toward proinflammatory with a deregulation of γ interferon, tumor necrosis factor α, interleukin 2 (IL2), PGE2, PGI1, thromboxanes, IL10, IL8, and C-X-C motif chemokine 10. These data have implications not only in ex vivo expansion of hBMSC but also in microenvironment tumor biology.