Researchers solve anti-aging mystery – Identify the gene responsible for cellular aging

Cell reprogramming can reverse aging which leads to a decline in the activities and functions of mesenchymal stem / stromal cells (MSCs). This is something scientists have known for some time. But what they did not understand is what molecular mechanisms are responsible for this reversal. A study published today in STEM CELLS seems to have solved this mystery. It not only improves knowledge about MSC aging and associated diseases, but also provides insight into the development of pharmacological strategies to reduce or reverse the aging process.

The research team, made up of scientists from the University of Wisconsin-Madison, relied on cell reprogramming – an approach commonly used to reverse cellular aging – to establish a model of genetically identical young and old cells for this study. “While concurring with previous findings on MSC rejuvenation through cell reprogramming, our study goes further by providing insight into how reprogrammed MSCs are molecularly regulated to improve cellular characteristics of aging,” the researcher explained. principal, Wan-Ju Li, Ph.D., faculty member of the Department of Orthopedics and Rehabilitation and the Department of Biomedical Engineering.

Researchers began by deriving MSCs from human synovial fluid (SF-MSC) – that is, fluid found in the knee, elbow, and other joints – and reprogramming them into induced pluripotent stem cells (iPSCs). ). Then they reverted those iPSCs back to MSCs, actually rejuvenating MSCs. “When we compared the reprogrammed MSCs to the non-rejuvenated parental MSCs, we found that aging-related activities were significantly reduced in the reprogrammed MSCs compared to those of their parental lines. This indicates a reversal of cellular aging, ”said Dr Li.

The team then performed an analysis of the cells to determine if there were any changes in overall gene expression resulting from the reprogramming. They found that the expression of GATA6, a protein that plays an important role in intestinal, pulmonary and cardiac development, was repressed in reprogrammed cells compared to control cells. This repression led to an increase in the activity of a protein essential for embryonic development called sonic hedgehog (SHH) as well as to the level of expression of another protein, FOXP1, necessary for the proper development of the brain, the heart and lungs. “Thus, we have identified the GATA6 / SHH / FOXP1 pathway as a key mechanism that regulates the aging and rejuvenation of MSC,” said Dr Li.

“The identification of the GATA6 / SHH / FOXP1 pathway in the control of MSC aging is a very important achievement.” Says Dr Jan Nolta, editor-in-chief of STEM CELLS. “Premature aging can thwart the ability to expand these promising cells while maintaining function for clinical use, and better knowledge of the pathways that control differentiation and senescence is very valuable.”

To determine which of the Yamanaka transcription factors (four reprogramming genes used to derive iPSCs) were involved in the repression of GATA6 in iPSCs, the team analyzed GATA6 expression in response to the suppression of each factor. This gave the information that only OCT4 and KLF4 are able to regulate the activity of GATA6, a conclusion consistent with that of several previous studies.

“Overall, we were able to demonstrate that SF-MSCs undergo substantial changes in properties and functions following cell reprogramming. These changes in iPSC-MSCs collectively indicate an improvement in cellular aging. More importantly, we were able to identify the GATA6 / SHH / FOXP1 signaling pathway as an underlying mechanism that controls activities related to cell aging, ”said Dr. Li.

“We believe our findings will help improve understanding of aging MSC and its importance in regenerative medicine,” he concluded.

Reference: “GATA6 Regulates Aging of Human Mesenchymal Stem / Stromal Cells” by Hongli Jiao, Brian E. Walczak, Ming-Song Lee, Madeleine E. Lemieux and Wan-Ju Li, November 30, 2020, STEM CELLS.
DOI: 10.1002 / stem.3297