Stem cells are undifferentiated cells that can develop into specialized cells. Given their unique regenerative abilities, stem cells offer new potentials for treating a wider variety of diseases, such as cancer, diabetes, heart disease, Parkinson's disease, muscle damage, and so on.

Figure. Sox2 suppresses mTOR transcription and initiates autophagy during cell reprogramming.

Macroautophagy is an evolutionarily conserved process that degrades cytoplasmic proteins and organelles to recycle cellular components for cell survival and tissue homeostasis. Previous studies did not show whether autophagy is involved in cellular reprogramming, i.e., conversion of a cell from one specific cell type to another. A recent study revealed the linkage between autophagy and reprogramming of somatic cells. Professor FAN Zusen and his colleagues at the Institute of Biophysics, Chinese Academy of Sciences discovered that autophagy is required for reprogramming of somatic cells to form induced pluripotent stem cells (iPSCs).

They found that during iPSC induction, autophagosomes appeared at first day after OSKM induction, and peaked on the following day. They observed that mammalian target of rapamycin (mTOR) is downregulated by Sox2 at an early stage of iPSC generation and that this transient downregulation of mTOR is required for autophagy and reprogramming to take place. In the absence of Sox2, mTOR remains at a high level and inhibits autophagy. Mechanistically, Sox2 binds to a repressive region on mTOR promoter to suppress mTOR expression. They identified that Sox2 recruits the NuRD complex to mediate transcriptional repression by using the specific binding sequence of Sox2. The silencing of the components of NuRD complex impairs autophagy and reprogramming of iPSC.

The researchers also detected enhanced autophagy at the four to eight cell stage of embryonic development, and a similar Sox2 and mTOR-mediated regulatory pathway operates in this context as well. Their findings revealed that Sox2-dependent temporal regulation of autophagy was a key step in cellular reprogramming processes.

This study provided new insight into the mechanisms of somatic reprogramming and suggested new way to promote efficiency of iPSC generation. Results of the study were published on Cell Stem Cell (November 7th issue, 2013) in an article entitled “Transient Activation of Autophagy via Sox2-Mediated Suppression of mTOR Is an Important Early Step in Reprogramming to Pluripotency”, and co-first authored by Drs. Shuo Wang and Pengyan Xia. The study was supported by grants from the National Natural Science Foundation of China, the Ministry of Science and Technology of China and the Chinese Academy of Sciences.

 

The article can be found at: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(13)00451-7#