Researchers have found a separate group of platelets that show up as people age and have overactive behavior and distinct molecular properties. This discovery could make it easier to develop medications that target these platelets.
As individuals get older, they become more susceptible to blood clotting diseases, where platelets stick together unnecessarily and can lead to serious health issues like strokes and cardiovascular disease. Scientists have been studying why this happens for many years, and their findings have contributed to the development of various blood-thinning medications currently available for treatment.is been: Why do platelet behavior and appearance change as we age?” said Forsberg. “We have discovered a distinct platelet population that is different in many ways from the previously well-characterized platelets circulating in the blood.”
The study, published in the journal Blood, could ultimately lead to new ways to diagnose, monitor, and treat age-related platelet defects that contribute to thrombosis, stroke, and heart attack, and worsen outcomes in surgery and transplantation. Forsberg’s team used state-of-the-art single-cell technologies and bioinformatics to analyze the transcriptome of individual platelets at different ages to discover the age-specific molecular signatures of the distinct platelet cells.
The study identified unique markers and pathways associated with the distinct platelet population, including increased expression of genes involved in DNA repair, genomic instability, and response to DNA damage stimuli.
“We hope that our findings will lead to new methods to diagnose, monitor, and treat age-related platelet defects, which will help to prevent the devastating effects of age-associated thrombosis and hemostasis,” Forsberg said. “And we are optimistic that our findings will contribute to the larger efforts in the scientific community to better understand aging and how to treat age-related diseases.”
The research was supported by funds from the National Institutes of Health and the American Heart Association, and the authors have filed a patent on the age-associated platelet population and its use as a diagnostic test.”Why do older people have such a high risk of clotting, stroke, and heart disease?” Forsberg asked. “We’ve discovered a completely new pathway that becomes more active as people age – troublemakers! This was never part of the conversation.”
The team’s findings were published in the journal Cell. The primary author, Donna Poscablo, a former Ph.D. student of Forsberg who is now a postdoctoral scholar at Stanford University, and her colleagues conducted these experiments at the Institute for the Biology of Stem Cells (IBSC) at UC Santa.
Platelet cells are an essential component of our blood, along with red and white blood cells. They are always present in the blood and play a crucial role in forming clots to stop bleeding when we get injured. However, as we age, the regulation of platelet cells can become disrupted. This can lead to two main issues – either the platelets become too reactive and form clots too frequently, or they don’t work effectively. Both of these scenarios can cause problems with managing bleeding and clotting, although hyperreactivity is a more common issue.
The article discusses the process of blood cell formation from hematopoietic stem cells and the impact of aging on these cells. It raises the question of why platelets created by less healthy hematopoietic cells are hyperreactive. Researchers at UC Santa Cruz explore a potential “shortcut” pathway in this process.The researchers investigated hematopoietic stem cells in order to answer this question. They used experiments to track the lineage of these cells in mice, and found that in older mice, some platelets did not follow the usual differentiation pathway. Instead, they took a “shortcut” pathway, bypassing some steps and becoming megakaryocyte progenitors directly. This discovery of an age-specific stem cell pathway is a first according to the researchers.Red blood cells are seen as one lineage that shares regulation and intermediate stages until the very end,” Forsberg said. “To see that the secondary platelet population were completely separated all the way from the stem cell level, only in aged mice, was really surprising.”
Although the population of platelets produced from the shortcut pathway are hyperreactive, the platelets produced from the main pathway continue to behave like the platelets in a young person.
“The gradual differentiation cascade maintains a youthful property, and I feel like that is also surprising within itself,” Poscablo said.
</di rnrnResearchers discovered that hyperreactive secondary platelets start being produced in mice around midlife, and their numbers increase as they age. The trigger for this secondary pathway production has not yet been identified. Interestingly, the production does not appear to be initiated by the aging environment itself. When a young hematopoietic stem cell is placed in an aged environment, the shortcut pathway is not activated. Similarly, when an aged hematopoietic stem cell is placed in a young environment, the old stem cells continue to function as they did before. This surprising finding shows that the trigger for the production of the hyperreactive secondary platelets is not directly related to the aging environment.”Age doesn’t impact the resilience of one pathway,” Forsberg stated. “One group of platelets remains unaffected by aging, while the other group we’ve identified is. Therefore, the entire phenomenon is not primarily caused by the environment, but by the differentiation path.”
Improving treatments
Identifying the existence of this secondary platelet population will assist researchers in developing new methods to target and regulate these problematic cells through their stem cells. Prior to this discovery, researchers had not attempted to target these upstream cells.
“With our expertise, we can explore how to target the hematopoietic Stem cell and now the megakaryocyte progenitor, which has never really been highlighted before as a place to target,” Poscablo said. Targeting these cells may not require the creation of new medications, but more simply inform the prescription of existing blood thinners such as Aspirin, which treat different patients to varying degrees even if they present with similar clotting-related symptoms. Using their mouse models, the researchers will identify which of the two populations of stem cells are more sensitive to Aspirin and the myriad of other platelet drugs on the market. The UCSC researchers are also currently working on findThe researchers are studying a secondary population of platelets in human cells, funded by the California Institute for Regenerative Medicine (CIRM). They are also receiving funding from the National Institutes of Health (NIH) to continue their study of how to manipulate and control this shortcut pathway in mouse models. Collaborators on this research included UCSC Assistant Professor of Applied Mathematics Vanessa Jönsson and University of Michigan Medical School’s Reheman Adili and Michael Holinstat. Current and former IBSC scholars on this project included Atesh Worthington (now at UC San Francisco), Stephanie Smith-Berdan, Marcel Rommel, and Bryc.The authors of this study include Donna M. Poscablo, Atesh K. Worthington, Stephanie Smith-Berdan, Marcel M.E. Rommel, Bryce A. Manso, Reheman Adili, Lydia Mok, Roman Reggiardo, Taylor Cool, Raana Mogharrab, Jenna Myers, Steven Dahmen, Paloma Medina, Anna E. Beaudin (currently at the University of Utah, Salt Lake City), and Scott Boyer.
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