Here, researchers explore the mechanisms governing changes in cell behavior during reprogramming. Many of the aspects of aging found in cells taken from old tissues can be reversed via the process of reprogramming these cells into induced pluripotent stem cells. Mitochondrial function is restored to youthful levels, for example, as well as much of the epigenetic signature that determines protein production and cell function. There are issues that are not addressed, such as mutations, but this effect of reprogramming is sufficiently interesting to have given rise to several research programs and the company Turn.bio, seeking to build a therapy on the basis of partially reprogramming cells to the point at which rejuvenation occurs.
Scientists know that cellular reprogramming can reverse the process of cellular aging that leads to a decline in the activities and functions of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms haven't been clear. Newly reported research has identified a key role for a protein known as GATA6, in this reversal process. Researchers used cellular reprogramming to establish a genetically identical young and old cell model. They began by isolating MSCs from human synovial fluid (SF-MSCs), and reprogrammed them into induced pluripotent stem cells (iPSCs) using the Yamanaka transcription factors. Then they differentiated these iPSCs back to MSCs, in effect rejuvenating the MSCs.
The scientists next conducted an analysis of the cells to determine if there were any changes in global gene expression resulting from the reprogramming. They found that the expression of GATA6, a protein that plays an important role in gut, lung, and heart development, was repressed in the reprogrammed cells compared with the control cells. This repression led to increased activity of a protein called sonic hedgehog (SHH) that is essential to embryonic development, as well as the expression level of another protein, FOXP1, which is necessary for proper development of the brain, heart, and lung.
To determine which of the Yamanaka transcription factors were involved in repressing GATA6 in the iPSCs, the team analyzed GATA6 expression in response to the knockdown of each factor. The results indicated that only OCT4 and KLF4 were able to regulate GATA6 activity, a finding that is consistent with that of several previous studies.