Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress

To better understand the mechanisms that regulate stem cell identity and function we sought to identify genes that are preferentially expressed by stem cells and critical for their function in multiple tissues. Prdm16 is a transcription factor that regulates leukemogenesis1, palatogenesis2, and brown fat development3–5, but which was not known to be required for stem cell function. We demonstrate that Prdm16 is preferentially expressed by stem cells throughout the nervous and hematopoietic systems and required for their maintenance. Prdm16 deficiency led to changes in reactive oxygen species (ROS) levels, increased cell death, altered cell cycle distribution, and stem cell depletion in the hematopoietic and nervous systems. In neural stem/progenitor cells, Prdm16 bound the Hgf promoter and in the absence of Prdm16 Hgf expression declined. Addition of recombinant HGF to culture partially rescued the increase in ROS levels and the depletion of Prdm16 deficient neural stem cells. Administration of the anti-oxidant, N-acetyl-cysteine, to Prdm16 deficient mice partially rescued defects in neural stem/progenitor cell function and neural development. Prdm16 therefore promotes stem cell maintenance in multiple tissues, partly by modulating oxidative stress.