New research into how embryonic stem cells (ESCs) renew themselves could pave the way for tissue and organ regeneration therapies.
ESCs are a type of stem cell with the unique ability to self-replicate indefinitely and can turn into any kind of cell type in the body, a potential called pluripotency. If this extraordinary ability could be understood and controlled it could be used to regenerate or replace damaged organs.
'It's an intriguing discovery in the field of stem cell biology and for researchers looking to develop therapies for tissue or organ regeneration.' said senior study author Dr Xiaolu Yang from Penn University in Philadelphia, Pennsylvania.
Dr Yang's team analysed ESCs from mice to study autophagy: the 'self-eating' mechanism used by cells to destroy unnecessary cellular material. They were especially interested in a type of autophagy called CMA which only occurs in the cells of mammals.
They found that regulating CMA is essential to the maintenance of ESCs pluripotency: it is kept at a low level by two cellular factors – Oct4 and Sox2 – both of which were previously known to be associated with pluripotency. These factors suppress a gene called LAMP2A which codes for a protein crucial for CMA. The team discovered that keeping CMA low is necessary to allow the cells to retain high levels of a molecule called alpha-ketoglutarate which is crucial to maintaining pluripotency.
When a stem cell starts differentiation, Oct4 and Sox2 levels decline, allowing LAMP2A activation, which causes CMA activity to increase. This in turn disruptes enzymes necessary for alpha-ketoglutarate production, allowing the cell to lose pluripotency and develop into the necessary cell type.
Although previous studies highlighted the significance of cell metabolism on stem cells fate determination, this is the first study describing the mechanism behind this process.
'This newly discovered role of autophagy in the stem cell is the beginning of further investigations that could lead to researchers and physician-scientists to better therapies to treat various disorders.' Dr Yang said.
The research was published in Science.