Cell reprogramming can reverse aging leading to a decline in the activities and functions of mesenchymal stem / stromal cells (MSCs). This is something that scientists have long known. But what they have not calculated is what molecular mechanisms are responsible for this reversal. A study released today in STEM CHEMICALS he seems to have solved this mystery. It not only enhances MSC’s aging knowledge and related diseases, but also provides insights into the development of pharmacological strategies to reduce or reverse the aging process.
The research team, which includes scientists at the University of Wisconsin-Madison, relied on cell reprogramming – a commonly used method to reverse cell aging – to establish a genetically identical old and young cell model for this study . “While we agree with previous findings in MSC replacement by cell reprogramming, our study goes further to provide insights into how reprogrammed MSCs are molecularly regulated to mitigate the cellular properties of aging,” the researcher explained lead, Wan-Ju Li, Ph.D., 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 multipurpose stem cells (iPSCs). They then returned these iPSCs back to MSCs, effectively renewing the MSCs. “When we compared the reprogrammed MSCs with the non-refurbished parent MSCs, we found that aging-related activities were greatly reduced in reprogrammed MSCs compared to those in their lineups parents. This is a sign of reversing cell aging, ”says Dr. Li.
The team next conducted cell analysis to determine if there were any changes in global gene expression resulting from the reprogramming. They found that expression of GATA6, a protein that plays an important role in the development of the gut, lungs and heart, is inhibited in the reprogrammed cells compared with the control cells. This repression led to increased protein activity essential to embryonic development called sonic hedgehog (SHH) as well as yet another protein expression level, FOXP1, which is necessary for the proper development of the brain, heart and the lungs. “We therefore identified the GATA6 / SHH / FOXP1 pathway as a key mechanism regulating MSC aging and renewal,” said Dr. Li.
“Identifying the GATA6 / SHH / FOXP1 pathway in the aging management of MSCs is a very important achievement.” Says Dr. Jan Nolta, Editor-in-Chief STEM CHEMICALS. “Premature aging can hinder the expansion of these promising cells while maintaining function for clinical use, and better knowledge of the pathways that control differentiation and senescence is invaluable.”
To determine which of the Yamanaka transcription factors (four reprogramming genes used to derive iPSCs) were involved in depressing GATA6 in the iPSCs, the team analyzed GATA6 expression in response to overexpression of each factor. This led to the knowledge that only OCT4 and KLF4 can regulate GATA6 activity, a finding consistent with the knowledge of several previous studies.
“Overall, we were able to demonstrate that SF-MSCs undergo significant changes in properties and functions as a result of cell reprogramming. These changes in iPSC-MSCs together indicate enhancement of cell aging. Most significantly, we were able to identify the GATA6 / SHH / FOXP1 signaling pathway as a primary mechanism controlling cell aging activities, ”said Dr. Li.
“We believe our findings will help improve the understanding of MSC aging and its significance in regenerative medicine,” he concluded.
Reference: “GATA6 regulates mesenchymal stem cell / human stromal aging” by Hongli Jiao, Brian E. Walczak, Ming – Song Lee, Madeleine E. Lemieux and Wan – Ju Li, 30 November 2020, STEM CHEMICALS.
DOI: 10.1002 / stem.3297