Satellite cells differentiate into muscle cells or renew themselves depending on the level of lipid droplets in the cell. Shihuan Kuang, a Purdue University animal science professor, has shown for the first time that fat inside adult muscle stem cells regulates their fate. (Purdue University image/courtesy of Shihuan Kuang) Image download
WEST LAFAYETTE, Ind. — For the first time, scientists have shown that the fat inside adult muscle stem cells regulates their fate.
Shihuan Kuang, a professor of animal science at Purdue University who led the team of scientists, said: “No one has ever seen such dynamics of lipid droplets in these muscle stem cells, so the examination was very important. This break is very interesting. “To then discover that they play such a powerful role in the fate of stem cells is remarkable. It has potential implications for muscular diseases, aging and animal science.”
Cells contain a variety of fats, or lipids, that are necessary for energy production, cell membrane construction, and chemical signaling. Special structures, called lipid droplets, safely store this cellular fat.
Instead of existing as a static pool of resources, the researchers found that the number of these droplets varied significantly within an individual cell and varied from cell to cell. The number of droplets also determines what the stem cell will become.
This finding, along with the newly identified role of lipids in other types of stem cells – including cancer stem cells – suggests that fat may be involved in more than previously thought. Kuang said. These findings are detailed in a paper in the journal Cell Reports.
The Purdue team studied satellite cells, a population of stem cells responsible for muscle development, growth, and regeneration. In adult muscle, these cells are maintained in a dormant state until injury occurs and they are called upon to work. They then reproduce through division, and some of the cells that have divided become muscle cells to replace damaged cells, in a process called differentiation. Others return to a state of inactivity through a process called self-renewal.
“Our study shows that stem cells with a higher number of lipid droplets continue to divide or continue to differentiate and become muscle cells, and those with a lower number of lipid droplets continue to divide,” says Kuang. back to replenish dormant stem cells for the next wound.” “In fact, during self-renewal, they somehow deplete or remove the lipid droplets, and in the dormant state contain nothing.”
They found that upon activation, droplets appeared, and as each cell divided, lipid droplets were not always evenly distributed. Some progeny cells from division have more drops than others, and this asymmetrical distribution leads to the division’s fate into the capacity for self-renewal or differentiation.
“These lipid droplet dynamics are important for maintaining a healthy balance of cells,” says Kuang. “We need new muscle cells to repair, but we don’t want stem cells to divide uncontrollably, like what happens in cancer. Depletion of lipid droplets is like a brake to prevent uncontrolled proliferation.”
In previous studies, Kuang’s team focused on both muscle and fat cells.
“Because we also study fat cells called adipocytes, we already had the tools to make this discovery,” he said. “In several routine cell staining, Feng Yue, a postdoctoral researcher in our group, noticed the dynamics of lipid droplets in stem cells. This was surprising as they were not known to be so abundant and dynamic in these cells at the time. We thought ‘Why are they here?’ We have to find out.”
The team used skeletal muscle stem cells in culture and mouse models to determine the function of lipid droplets. The team inhibited the formation of lipid droplets and then inhibited their use to see how these changes would impact cell function.
Yue, now an assistant professor at the University of Florida, said: “The results were astounding because too many or too few lipid droplets disrupted stem cell homeostasis. “This suggests that in the future we may be able to stimulate the regenerative function of stem cells by manipulating the dynamics of lipid droplets in satellite cells.”
Team members and co-authors also include Stephanie N. Oprescu, PhD student in the Department of Biological Sciences; Jia Manqiu, Lijie Gu, Lijia Zhang and Jingjuan Chen, PhD students in animal science; Naagarajan Narayanan, postdoctoral researcher in agricultural and biological engineering; and Meng Deng, assistant professor of agricultural and biological engineering.
Kuang plans to further investigate the role of lipid droplets in muscle repair.
“We still do not fully understand the upstream regulators and downstream mediators of lipid droplets in muscle stem cells,” he said. “There may be secondary metabolites formed from the breakdown of lipid droplets that are also important. These fats can be more than just a source of energy for cells.”
The National Institutes of Health (NIH-R01AR071649; R03AR068108; F31AR077424; P30CA023168; S10DO20029), the Muscular Dystrophy Association (MDA516161), and the United States Department of Agriculture (NC1184) funded this work.
Writer: Elizabeth K. Gardener; 765-441-2024; ekgardner@purdue.edu
Source: Thach Hoan Quang; 765-494-8283; skuang@purdue.edu
ABSTRACT
Lipid droplet dynamics regulate adult muscle stem cell fate
Feng Yue, Stephanie N. Oprescu, Jiamin Qiu, Lijie Gu, Lijia Zhang, Jingjuan Chen, Naagarajan Narayanan, Meng Deng and Shihuan Kuang
LINK TO PAPER:
Lipid droplet (LD) is the center of fatty acid metabolism in the cell. Here, we define the dynamics and explore the role of LD in skeletal muscle satellite cells (SCs), a subpopulation of stem cells responsible for muscle regeneration. In newly divided SCs, LD was unevenly distributed in sister cells exhibiting asymmetric cell fate, as LDShort cells self-renewal while LDHigh cells committed to differentiation. When implanted in regenerative muscle, LDShort cells outperform LDHigh cells during self-renewal and regeneration in vivo. Pharmacological inhibition of LD biogenesis or genetic inhibition of LD catabolism through knockout of the Pnpla2 gene (encoding ATGL, lipolysis rate-limiting enzyme) disrupts cellular homeostasis. cells and impair the regenerative capacity of SCs. Dysfunction of Pnpla2-null SC that is associated with energy deprivation and oxidative stress can be partially rescued by antioxidant (N-acetylcysteine) treatment. These results establish a direct link between LD dynamics and stem cell fate determination.
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