Researchers solve anti-aging mystery – identify genes responsible for cellular aging

Cellular reprogramming can reverse aging which causes a decline in the activities and functions of mesenchymal stem / stromal cells (MSCs). This is something that scientists have known for some time. But they did not know which molecular mechanisms are responsible for this reversal. A study released today Stem cell Appears to solve this mystery. This not only enhances the knowledge of MSC aging and related diseases, but also provides insight into developing pharmacological strategies to reduce or reverse the aging process.

The research team, made up of scientists at the University of Wisconsin – Madison to establish genetically identical young and old cell models for this study, relies on cellular reprogramming – a commonly used approach to reverse cell aging . “Agreeing with previous findings in rejuvenation of MSCs by cellular reprogramming, our study goes on to provide information on how reprogrammed MSCs are molecularly regulated to modulate cellular hallmarks of aging. Goes, ”explained lead-maker, Wan-ju Lee, PhD. A faculty member in the Department of Orthopedics and Rehabilitation and Biomedical Engineering.

Mesenchymal stem / stromal cells

When mesenchymal stem / stromal cells (MSCs) age, the transcription factor GATA6 is rapidly produced in the cell to induce an aging response. By transcription factor-based cellular reprogramming, aged MSCs are rejuvenated with decreased GATA6 effects on cellular aging. Sincerely: Alfred Press

Researchers began by deriving MSCs from human synovial fluid (SF-MSCs) – that is, fluids found in the knee, elbow, and other joints – and reproducing them in induced pluripotent stem cells (iPSCs). They then returned these IPSCs back to MSCs to rejuvenate MSCs. He stated, ‘When we compared re-upgraded MSCs to non-rejuvenated parental MSCs, we found that age-related activities were significantly reduced in reprogrammed MSCs compared to their parental lines. It indicates cell aging, ”Dr. Lee said.

The team then analyzed the cells to determine if reprogramming resulted in any changes in global gene expression. They found that expression of GATA6, a protein that plays a key role in gut, lung, and heart development, was suppressed in reprogrammed cells compared to control cells. This suppression increased the level of expression of FOXP1, another protein required for the proper development of the brain, heart, and lungs, along with an increase in activity of proteins required for embryonic development called sonic hedgehog (SHH). “Thus, we identified the GATA6 / SHH / FOXP1 pathway as a major mechanism that regulates MSC aging and rejuvenation,” Dr. Lee said.

“Identification of the GATA6 / SHH / FOXP1 pathway is a very important modification in controlling the age of MSCs.” Dr. John Knowlta, Editor-in-Chief, said Stem cell. “Premature aging can thwart the ability of these promising cells to expand while retaining function for clinical use, and enhanced knowledge and higher levels of pathways that control differentiation are highly valued.”

To determine which Yamanaka transcription factors (the four reprogramming genes used to elicit iPSC) were involved in repressing GATA6 in iPSC, the team analyzed GATA6 expression in response to the knockdown of each factor. This provided information that only OCT4 and KLF4 are capable of regulating GATA6 activity, which is consistent with several previous studies.

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

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

Reference: “GATA6 regulates the aging of human mesenchymal stem / stromal cells by Hongli Xiao, Brian E. Walcak, Ming Lee Song Li, Madeleine E. Lemieux and Wan Li Xu Li, 30 November 2020.” Stem cell.
DOI: 10.1002 / stem .297

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