While stem cells have either been hailed as either the holy grail of regenerative medicine or harbingers of some future techno-genetic dystopia, the reality is that using stem cells is fraught with numerous practical and theoretical obstacles. Current studies into the use of stem cells strongly suggest that stem-cell based therapies have immense clinical potential, from growing tissues or organs out of undifferentiated stem cells to developing cures for a host of untreatable diseases. However, the exact mechanisms underlying stem cells’ ability to differentiate into different cell types and thereby developing more effective mechanisms to control this differentiation have been a major hurdle to advancing the application of stem cells.

Recently, ZHENG Ping’s research group at the Kunming Institute of Zoology (KIZ) of Chinese Academy of Sciences began investigating applications of pluripotent stem cells (PSCs). Studies of these cells in culture found that they seemed to frequently mutate, inhibiting their further application in stem-cell based therapies. Compared with differentiated cells, pluripotent cells appear to possess some unique abilities of maintaining the stability of their genetic material by repairing damaged DNA, a process known as DNA damage response (DDR). DDR is a fundamental and evolutionarily conserved mechanism needed to preserve the genomic integrity of cells, but this process is extremely complex, involving several highly coordinated response networks that eventually trigger an arrest of the cell cycle and initiate repair of the DNA.

DDR has been studied intensively in somatic cells, little research has been done on the DDR network of pluripotent stem cells. The existing reports indicate that these cells use markedly distinct strategies to deal with DNA damage, but the molecular basis of these regulatory mechanisms remains unknown, as are the particular factors involved in stem cell stability. Better understanding of these underlying properties and mechanisms should then help solve several key problems in further medical applications of stem cells.

Investigating the regulators of stem cells, ZHENG’s group identified Filia as a novel multifunctional regulator that helps to maintain the stability of embryonic stem cells in mice. The expression of Filia in pluripotent cells appears to play a key role in maintaining the genetic stability of the cells, so much so that ZHENG’s team found that genetic mutations increase rapidly when Filia is not present. The research team also found that Filia helps to regulate DDR through multiple pathways, including DDR signaling, cell cycle checkpoints and damage repair, stem cell differentiation, and apoptosis.

The results showed that stem cells began experiencing genetic instability once Filia was removed, which was accompanied by a resistance to apoptosis, and increased risk of mutation. ZHENG’s group further demonstrated the Filia interacts with PARP1, which is an enzyme related to cell stability, and that it is located on the centrosome and is able to move to the DNA damage sites as needed.  

The findings mark a major step in the brave new world of stem-cell based therapies, providing a both an enhanced understanding of the mechanisms regulating DDR and genomic stability in stem cells and offering researchers Filia as a simple and elegant marker that can be used to evaluate the stability of pluripotent cells. The study was published in Cell Stem Cell.

This project received support of the Chinese Academy of Sciences and National Natural Science Foundation.