Researchers Discover New Aging Gene Using Mesenchymal Stem Cells

Mesenchymal stem cells are emerging as a promising therapeutic approach for a wide range of autoimmune disorders and degenerative diseases due to their multi-differentiation and immune regulation ability. However, the aging of these cells is regarded as a major challenge for MSC therapies and tissue engineering. A research published on December 1st in Stem Cells journal sheds light on an important pathway that may play a critical role in the aging of MSCs. This crucial finding is crucial for developing pharmacological strategies to ameliorate MSC aging.

Behind the Scenes

Since the discovery of Yamanaka factors, a cocktail of proteins important for turning an aging cell into a younger one, many scientists have started using these proteins on aged cells to make them young and then study the process of aging. This process is called cellular reprogramming. “Reprogramming of the cells can rejuvenate aged cells through altering senescence-associated cellular and molecular characteristics.”

Using this method on mesenchymal stem cells (MSC) derived from human synovial fluid-a fluid found in the knee, elbow, and other joints, the group generated induced pluripotent stem cells (iPSCs) and then differentiated them into MSCs (iPSC-MSC) again. The newly differentiated MSC line (iPSC-MSC), when compared to the line derived from synovial fluid (SF-MSC), “underwent significantly more cumulative population doublings in long term culture.” This means they divided more than the original line.

Also, the iPSC-MSCs, when forced to differentiate, made more osteocytes and chondrocytes, unlike SF-MSC, which, when differentiated, made more fat cells called adipocytes. These features are indicative of rejuvenated or younger MSCs.

GATA6 Mediates Cell Aging

To understand the changes brought about by cellular reprogramming, the group compared gene expression profiles between the older MSC population, SF-MSC, and the younger MSC population, iPSC-MSCs. They found that expression of GATA6, a protein that plays an important role in gut, lung, and heart development, was reduced in the rejuvenated cells compared to the ones derived from synovial fluid.

To evaluate the functional role of GATA6 in regulating aging, the group genetically reduced its levels in iPSC-MSC. This manipulation resulted in upregulation of osteogenesis and chondrogenesis, a sign of younger MSC with the concurrent increase in mRNA expression of bone-associated markers. This was seen with a simultaneous reduction in adipogenesis- a sign of older MSC.

Low GATA6 expression was accompanied by high expression of a protein essential for embryonic development called sonic hedgehog (SHH) as well as a protein important for brain, heart, and lung development called FOXP1 in iPSC-MSC cells. However, the relation between these three factors got clear when knockdown of GATA6 increased the expression of SHH as well as FOXP1. This experiment suggested that GATA6 is an upstream inhibitory regulator of both SHH signaling and FOXP1. Further experiments such as a dose-dependent increase in SHH levels increased FOXP1 levels but not GATA6. This delineated the pathway wherein GATA6 is the master regulator that regulates SHH signaling, which in turn controls downstream FOXP1.

Future Implications

MSCs are a rare cell population in the body whose number is usually no more than 0.01% of the total cell count. Because of their low numbers, the use of MSCs in various clinical applications, including regenerative medicine, relies on their strong proliferative ability in vitro to produce later generations with comparable regenerative capabilities. In vitro, MSCs are proliferated in a process called “passage.”

But multiple cycles of passage are accompanied by senescence, which potentially deteriorates MSC fitness to the point where the residual stem cell features are compromised and insufficient to support long-term tissue or organ regeneration. This study enhances the knowledge about the pathways that control senescence in MSCs. It demonstrates the contribution of an essential pathway, GATA6/SHH/FOXP1, in MSC senescence. This information will help control the aging of MSCs in clinical use and help in the development of pharmacological agents for reversing aging.

By Ruchi Jhonsa, Ph.D.

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References

1. https://www.eurekalert.org/pub_releases/2020-11/ap-rig112420.php
2. https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/stem.3297

Author

Ruchi Jhonsa