Vitamin A-derived compound may restore platelet production in ITP
ATRA improves platelet counts in mouse models of disease
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Treatment with all-trans retinoic acid (ATRA), a compound derived from vitamin A, may help restore production of clot-promoting platelets in people with immune thrombocytopenia (ITP), according to a study.
Researchers found that the compound improved the ability of megakaryocytes — the large cells in the bone marrow responsible for producing platelets — to form proplatelets, branch-like extensions that break apart to release platelets into the bloodstream. The effects appear to be mediated by ATRA’s ability to restore the HIF-1alpha/SPHK2/S1P signaling pathway, which researchers found to be disrupted in ITP.
In a mouse model of ITP, ATRA boosted proplatelet production in the bone marrow and increased platelet counts.
“These findings reveal that ATRA targets the HIF-1[alpha]/SPHK2/S1P pathway to improve [proplatelet formation] dysfunction, offering mechanistic insights into its clinical efficacy in ITP,” the researchers wrote.
The study, “ATRA improves megakaryopoiesis in immune thrombocytopenia through up-regulating the HIF-1α/SPHK2/S1P pathway,” was published in Science Advances.
Platelet problems in the marrow
ITP occurs when the immune system mistakenly targets and destroys platelets, circulating cell fragments that help blood clot, leading to low platelet levels and an increased risk of bleeding. But growing evidence suggests the disease is also driven by problems in platelet production within the bone marrow, where blood cells are made.
In particular, megakaryocytes appear less able to complete the final steps needed to release platelets. Normally, these cells extend proplatelets into nearby blood vessels, where they fragment into new platelets that are released into the bloodstream. Previous studies have shown that this process is impaired in ITP, although the exact mechanism has remained unclear.
Researchers previously found that ATRA treatment could improve platelet counts and enhance responses to standard therapies in some people with ITP. But how the therapy directly affects megakaryocytes and platelet production has not been fully understood.
To learn more, a team of researchers in China collected bone marrow samples from 30 adults with newly diagnosed ITP and 30 healthy volunteers between June 2019 and October 2021.
When the researchers grew megakaryocytes from healthy volunteers in the lab, the cells readily started forming proplatelets and releasing new platelets. But megakaryocytes from people with ITP struggled to form these extensions, suggesting a defect in the final stages of platelet production.
Looking more closely, the scientists found megakaryocytes from people with ITP also showed abnormalities in the cytoskeleton, the internal dynamic network of protein fibers that gives cells structure and helps them change shape and move.
The researchers then began tracing the potential causes of these defects. They found that people with ITP had lower levels of the signaling molecule sphingosine-1-phosphate (S1P) in their bone marrow than healthy volunteers.
That drop in S1P appeared important because the signaling molecule has been linked to platelet formation. The researchers found that S1P binds to a receptor on the surface of megakaryocytes, S1PR1, effectively signaling the cells to begin forming proplatelets.
When the researchers blocked S1PR1 in healthy megakaryocytes, these lost much of their ability to form proplatelets. But activating S1PR1 in megakaryocytes from people with ITP helped restore proplatelet formation.
These effects appeared to depend on Rac1, a protein involved in reorganizing the cytoskeleton so that cells can form extensions. When Rac1 was blocked, the benefit of S1PR1 activation disappeared, and megakaryocytes from people with ITP once again struggled to form proplatelets. Similarly, blocking Rac1 in healthy megakaryocytes impaired their ability to form proplatelets.
Lower S1P levels in the bone marrow of people with ITP seemed to stem from problems even further upstream. Megakaryocytes from people with ITP had lower levels of HIF-1 alpha than healthy cells. HIF-1 alpha is a protein that helps cells respond and adapt to low-oxygen conditions. This is particularly important because megakaryocytes develop in the bone marrow, which is naturally a low-oxygen (hypoxic) environment.
When the researchers reduced HIF-1α levels in healthy megakaryocytes, levels of SPHK2 — the enzyme needed to produce S1P — dropped, along with S1P levels and proplatelet formation. By contrast, boosting HIF-1α activity in megakaryocytes from people with ITP increased SPHK2 and S1P levels and improved the cells’ ability to form proplatelets.
When megakaryocytes from people with ITP were treated with ATRA in the lab, the vitamin A-derived compound increased HIF-1α and SPHK2 levels, boosted S1P production, and improved proplatelet formation. But when HIF-1α was blocked, these benefits largely disappeared, suggesting the pathway plays a central role in ATRA’s effects.
In a mouse model of ITP, ATRA treatment increased platelet counts, improved proplatelet formation in the bone marrow, and boosted HIF-1α and SPHK2 levels.
“These results uncover a previously unrecognized mechanism of ITP [disease development] and elucidate the molecular basis of ATRA’s therapeutic effects in patients with ITP,” the researchers wrote.
