Researchers say they’ve identified gene responsible for cellular aging

Researchers say they've identified gene responsible for cellular aging

Cellular reprogramming can reverse the aging that leads to a decline in the activities and functions of mesenchymal stem/stromal cells (MSCs). This is something that scientists have known for a while. But what they had not figured out is which molecular mechanisms are responsible for this reversal. A study released today in STEM CELLS appears to have solved this mystery. It not only enhances the knowledge of MSC aging and associated 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, relied on cellular reprogramming – a commonly used approach to reverse cell aging – to establish a genetically identical young and old cell model for this study. “While agreeing with previous findings in MSC rejuvenation by cellular reprogramming, our study goes further to provide insight into how reprogrammed MSCs are regulated molecularly to ameliorate the cellular hallmarks of aging,” explained lead investigator, Wan-Ju Li, Ph.D., a faculty member in the Department of Orthopedics and Rehabilitation and the Department of Biomedical Engineering.

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

The team 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 to the control cells. This repression led to an increase in the activity of a protein essential to embryonic development called sonic hedgehog (SHH) as well as the expression level of yet another protein, FOXP1, necessary for proper development of the brain, heart and lung. “Thus, we identified the GATA6/SHH/FOXP1 pathway as a key mechanism that regulates MSC aging and rejuvenation,” Li said.

“Identification of the GATA6/SHH/FOXP1 pathway in controlling the aging of MSCs is a very important accomplishment,” said 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 enhanced knowledge about the pathways that control differentiation and senescence is highly valuable.”

To determine which of the Yamanaka transcription factors (four reprogramming genes used to derive iPSCs) were involved in repressing GATA6 in the iPSCs, the team analyzed GATA6 expression in response to the knockdown of each factor. This yielded the information that only OCT4 and KLF4 are able to regulate GATA6 activity, a finding consistent with that of 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 amelioration of cell aging. Most significantly, we were able to identify the GATA6/SHH/FOXP1 signaling pathway as an underlying mechanism that controls cell aging-related activities,” Li said.

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

The full article, “GATA6 regulates aging of human mesenchymal stem/stromal cells,” can be accessed at https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/stem.3297.



from ScienceBlog.com https://ift.tt/2Ju04s6

Comments

Post a Comment

Popular

Words Matter When Discussing Alcohol Issues: A New Stigma-Free Vocabulary for Better AUD Outcomes

Image
Word choice may seem out of place among the myriad factors that can influence outcomes for a complex condition like alcohol use disorder (AUD). In fact, the stigma created by the language that is used to describe alcohol problems can decrease many people’s willingness to seek help for alcohol problems. It also can affect how people with AUD are treated in all aspects of life. “Stigmas are the negative attitudes toward people that are based on certain distinguishing characteristics,” says National Institute on Alcohol Abuse and Alcoholism (NIAAA) Director George F. Koob, Ph.D. “More than a decade of research has shown that stigma contributes significantly to negative health outcomes and can pose a barrier to seeking treatment for mental illness or substance use disorders.” In the United States, nearly 90 percent of people with substance use disorders and 35 percent of people with serious mental illness do not receive treatment. In a recent article published in  Neuropsychopharma...
Read more

‘Massive-scale mobilization’ necessary for addressing climate change, scientists say

Image
A year after a global coalition of more than 11,000 scientists declared a climate emergency, Oregon State University researchers who initiated the declaration released an update today that points to a handful of hopeful signs, but shares continued alarm regarding an overall lack of progress in addressing climate risks. “Young people in more than 3,500 locations around the world have organized to push for urgent action,” said Oregon State University’s William Ripple, who co-authored “The Climate Emergency: 2020 in Review,” published today in Scientific American. “And the Black Lives Matter movement has elevated social injustice and equality to the top of our consciousness. “Rapid progress in each of the climate action steps we outline is possible if framed from the outset in the context of climate justice – climate change is a deeply moral issue. We desperately need those who face the most severe climate risks to help shape the response.” One year ago, Ripple, distinguished profess...
Read more

Researchers advance science behind gut health and prebiotics

Image
When it comes to improving human gut health, approaches and the success of these approaches are based largely on an individual’s gut ecosystem: the bacteria present, its diversity and other factors. Therefore, trying to improve gut health through application of prebiotics or probiotics can have wildly variable results based on gut flora composition. Bruce Hamaker , director of the Whistler Center for Carbohydrate Research and Distinguished Professor of Food Science, and Thaisa Moro Cantu-Jungles, his postdoctoral research associate, recently discovered a way to select prebiotic fibers that have the potential to provide improvement of gut health where everyone would benefit. Their study, conducted in vitro, showed an increase in butyrate-producing bacteria with a selected fiber using this new approach. Butyrate is a short-chain fatty acid that supports many of the body’s essential functions from regulating the immune system to digestive health. In donors’ gut flora where these bacter...
Read more