New discovery could hold the key to regenerative therapies and Longevity.
The self-eating ability of cells could uncover new regenerative therapies as a team of Penn Medicine researchers have found that autophagy in embryonic stem cells and a related metabolite could prove to be new therapeutic targets to repair or regenerate damaged cells and organs.
Longevity.Technology: Studies have shown that autophagy has a vital role in the regulation of animal lifespan; autophagy removes oxidative damage and dysfunctional cell machinery, both of which cause aging at a cellular level, so autophagy prolongs lifespan. If we could tap into autophagy’s regenerative ability, therapies that extend both lifespan and healthspan could be developed.
Autophagy, or self-eating, is a process that all cells go through to help destroy bacteria and viruses after an infection. In addition, aging clogs up cells with broken and dysfunctional organelles and proteins and the autophagy process attempts to keep these to a minimum. When autophagy fails – and unwanted proteins build up – neurodegenerative conditions such as dementia and Huntington’s Disease can be caused.
The more we understand exactly how pluripotency works and is kickstarted and how cells use this regenerative power, the more we can adapt the process for therapy.
Autophagy in embryonic stem cells is known as chaperone-mediated autophagy (CMA); CMA is unique to mammals and its physiological role is still unclear. The new preclinical study by Penn Medicine shows, for the first time, how the stem cells keep CMA at low levels in order to promote self-renewal. Stem cells are pluripotent, meaning they can differentiate into any cell type. When a stem cell is ready, it switches off the CMA suppression and differentiates into a specialised cell.
The research team used metabolomic and genetic laboratory techniques on mouse embryonic stem cells to investigate the significant changes that take place while in a pluripotent state and subsequent differentiation. They found that CMA activity is kept at a minimum due to two cellular factors which are crucial for pluripotency. These factors, Oct4 and Sox2, suppress the gene LAMP2A, which instructs how to make the protein lysosomal associated membrane protein-2 which is necessary in CMA.
The researchers found that when CMA activity is minimised, the stem cells can maintain high levels of alpha-ketoglutarate, a metabolite that is vital for reinforcing a cell’s pluripotent state. When the cell begins the differentiation process, a reduction in Oct4 and Sox2 trigger the upregulation of CMA, which in turn degrades key enzymes responsible for the production of alpha-ketoglutarate.
The chain reaction results in a reduction in alpha-ketoglutarate levels and an increase in other cellular activities that encourage cell differentiation. The research team concluded from their results that CMA and alpha-ketoglutarate dictate the fate of embryonic stem cells.
“… intervening or guiding these functions could be a powerful way to increase the efficiency of regenerative medicine approaches …”
“It’s an intriguing discovery in the field of stem cell biology and for researchers looking to develop therapies for tissue or organ regeneration,” said senior study author Xiaolu Yang, PhD, a professor of Cancer Biology at the Abramson Family Cancer Research Institute in the Perelman School of Medicine at the University of Pennsylvania.
He added: “We reveal two novel ways to potentially manipulate the self-renewal and differentiation of stem cells: CMA and a metabolite, known as alpha-ketoglutarate, that is regulated by CMA. Rationally intervening or guiding these functions could be a powerful way to increase the efficiency of regenerative medicine approaches [1].”
Stem cells have been used in several regenerative therapies, including heart failure, wound repair and organ transplantation [2]. They can also be used to create tissue-specific cells to test new drugs. The more we understand exactly how pluripotency works and is kickstarted and how cells use this regenerative power, the more we can adapt the process for therapy.
Professor Yang commented: “This newly discovered role of autophagy in the stem cell is the beginning of further investigations that could lead to researchers and physician-scientists to better therapies to treat various disorders [3].”
[1] https://www.sciencedaily.com/releases/2020/07/200723143722.htm
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691074/
[3] https://phys.org/news/2020-07-self-eating-stem-cells-key-regenerative.html
