New research from the University of Wisconsin-Madison, published in Stem Cells, has identified a gene which regulates the ageing of human mesenchymal stem/stromal cells (MSCs).
Cellular reprogramming can reverse ageing in Mesenchymal stem/stromal cells (MSCs). However, the molecular mechanisms by which this is achieved are not well understood. This recent study supported previous findings, demonstrating that rejuvenation was possible by cellular reprogramming. Furthermore, their findings enhanced the understanding of MSC ageing and associated disease. These results provide insight into potential pharmacological strategies to reduce or reverse the ageing process.
The researchers extracted MSCs from human synovial fluid and reprogrammed them into induced pluripotent stem cells (iPSCs). They then transformed these iPSCs back into MSCs, in effect rejuvenating the MSCs. When comparing the rejuvenated MSCs to the original, non-rejuvenated cells, they found the cellular hallmarks of ageing were greatly reduced in reprogrammed cells. This reduction in ageing-related activities suggests a reversal of cell ageing has occurred.
Next, the scientists genetically analysed cells to investigate any changes in global gene expression as a result of the rejuvenation. They found that the expression of the GATA6 protein was repressed in reprogrammed cells.
The repression of GATA6 also led to an increase in the activity of the sonic hedgehog (SHH) protein and the FOXP1 protein, both essential for early development. Thus, the GATA6/SHH/FOXP1 pathway appears to be a key mechanism which regulates MSC ageing and rejuvenation.
Finally, the team confirmed that OCT4 and KLF4 (two of the four reprogramming genes used to derive iPSCs) were able to regulate GATA6 activity. This is consistent with several previous studies.
Overall, the study demonstrated that MSCs undergo substantial molecular and genetic changes as a result of cellular reprogramming. These changes indicate the amelioration of cell aging. Most significantly, the outlining of the GATA6/SHH/FOXP1 pathway as a mechanism for cellular age-related activities could have broad implications in regenerative medicine.