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Cellular reprogramming can reverse aging leading to a decline in mesenchymal stem / stromal cell (MSC) activities and functions. This is something scientists have known for some time. But what they didn’t understand is which molecular mechanisms are responsible for this reversal. A study published today in STAMINA CELLS seems to have solved this mystery. Not only does it improve knowledge of MSC aging and associated diseases, it also provides insight into the development of drug 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 genetically identical young and old cell model for this study. “While agreeing with previous findings on rejuvenating MSCs by cellular reprogramming, our study goes further to provide insight into how reprogrammed MSCs are molecularly regulated to improve the cellular hallmarks of aging,” explained lead researcher, Wan- Ju Li, Ph.D., a lecturer in the Department of Orthopedics and Rehabilitation and the Department of Biomedical Engineering.
As mesenchymal stem / stromal cells (MSCs) age, the transcription factor GATA6 is increasingly produced in the cell to induce the aging response. Through cellular reprogramming based on transcription factors, aged MSCs are rejuvenated with a reduction in the effects of GATA6 on cellular aging. Credit: AlphaMed Press
The researchers began by deriving MSCs from human synovial fluid (SF-MSC), which is the fluid found in the knee, elbow, and other joints, and reprogramming them into induced pluripotent stem cells (iPSCs). Then they restored these iPSCs to MSC, effectively rejuvenating the MSCs. “When we compared reprogrammed MSCs with non-rejuvenated parental MSCs, we found that aging-related activities were significantly reduced in reprogrammed MSCs compared to those in their parental lines. This indicates a reversal of cellular aging, ”said Dr Li.
The team then conducted a cell analysis to determine if there were any changes in global gene expression resulting from reprogramming. They found that the expression of GATA6, a protein that plays an important role in the development of the gut, lungs and heart, was repressed in the 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) and to the level of expression of another protein, FOXP1, which is necessary for proper development of the brain, heart and lung. . “Therefore, we have identified the GATA6 / SHH / FOXP1 pathway as a key mechanism that regulates the aging and rejuvenation of MSCs,” said Dr. There.
“The identification of the GATA6 / SHH / FOXP1 pathway in controlling MSC aging is a very important achievement.” Said Dr. Jan Nolta, chief editor of STAMINA CELLS. “Premature aging may hinder the ability to expand these promising cells while maintaining function for clinical use, and a better understanding of the pathways that control differentiation and senescence is extremely 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 the expression of GATA6 in response to the knockdown of each factor. This yielded the information that only OCT4 and KLF4 are able to regulate the activity of GATA6, a finding consistent with that of several previous studies.
“In general, we have been 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 an improvement in cellular aging. More significantly, we were able to identify the GATA6 / SHH / FOXP1 signaling pathway as an underlying mechanism that controls cell aging-related activities, ”said Dr Li.
“We believe our findings will help improve understanding of MSC aging and its significance 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, 30 November 2020, STAMINA CELLS.
DOI: 10.1002 / stem.3297
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