Metformin limits the tumourigenicity of iPS cells without affecting their pluripotency

Abstract

The antidiabetic drug metformin efficiently circumvents the dilemma that in reducing the tumourigenicity of stem cells, their essence, specifically their pluripotency, must also be sacrificed. Metformin prevents the occurrence or drastically reduces the size and weight of teratoma-like masses after the transplantation of induced pluripotent stem (iPS) cells into immunodeficient mice. Yet, iPS cells implanted into metformin-treated mice retain full pluripotency, as they produce the same number of distinct tissue types derived from the three embryonic germ layers that is observed in untreated mice. Mechanistically, metformin appears to suppress the Oct4-driven compartment of malignant stem cells responsible for teratocarcinoma growth while safeguarding an intact, Oct4-independent competency to generate terminally differentiated tissues. Metformin's ability to efficiently and specifically control the tumourigenic fate of teratoma-initiating iPS cells without interfering with their pluripotency not only has implications for the clinical use of iPS cells but also in stem cell biology, cancer and ageing.