Research indicates that cellular reprogramming may be able to reverse the aging that leads to the decline in the activities and functions of mesenchymal stem/stromal cells, but scientists have not been able to figure out which molecular mechanisms are responsible for this reversal.
A study recently published in STEM CELLS may have solved this mystery, enhanced the knowledge of MSC aging and associated disease, and provided insight into developing pharmacological strategies designed to reduce or reverse the aging process.
For this study cellular reprogramming approaches were utilized to establish a genetically identical young and old cell model. “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.
Cell analysis was conducted to determine if there were any changes in global gene expression resulting from the reprogramming; expression of the protein GATA6 that plays important roles in the gut, lung, and heart development was found to be repressed in the reprogrammed cells as compared to the control cells. Repression of GATA6 led to increased activity of the sonic hedgehog (SHH) protein that is essential to embryonic development as well as the expression levels of FOXp1 proteins required 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,” Dr. 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.”
In order to determine which of the 4 Yamanaka transcription factors used to reprogram genes to derive iPSCs were involved in repressing GATA6 in the iPSCs, the expression of GATA6 was analyzed in response to the knockdown of each factor. The analysis revealed that only OCT$ and KLF4 were able to regulate GATA6 activity, this finding is 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 signalling pathway as an underlying mechanism that controls cell aging-related activities,” Dr. Li said.
“We believe our findings will help improve the understanding of MSC aging and its significance in regenerative medicine,” he concluded.
