Scientists find new treatment path to improve blood clotting in ITP
Blocking enzyme called MELK may boost production of platelets in blood
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Blocking the activity of an enzyme known as MELK may help boost the production of platelets — tiny cell fragments that improve blood clotting and stop bleeding after an injury — in people with immune thrombocytopenia (ITP), a study suggests.
According to the researchers, inhibiting this enzyme could prove to be a way to reduce bleeds in people with ITP, an autoimmune condition that, in severe cases, can be marked by bleeding in the skin or internal organs.
The scientists discovered that MELK acts like a brake on the maturation of megakaryocytes, the cells in the bone marrow that give rise to platelets. Inhibiting MELK released the brake, helping megakaryocytes mature and increasing the creation of platelets.
“These findings suggest that MELK inhibition promotes [megakaryocyte] maturation and platelet production, … providing a potential for the development of therapeutic options for ITP,” the scientists wrote.
The study, “MELK inhibition promotes megakaryopoiesis and platelet recovery in models of immune thrombocytopenia through ERK/cofilin signaling,” was published in the journal Cell Reports by a team of scientists in China.
In ITP, the immune system mistakenly attacks and destroys platelets, which normally circulate throughout the bloodstream and move to the site of any injuries. The lack of platelets in ITP, which is known as thrombocytopenia, increases the risk of easy bruising and bleeding among patients.
Beyond platelet destruction, studies suggest that impaired maturation of megakaryocytes, specialized bone marrow cells where platelets get their start, plays a significant role in ITP development. Still, the exact mechanisms underlying it are not fully understood.
Investigating mechanisms underlying blood clotting pathways
To learn more, the scientists first analyzed publicly available gene expression (activity) datasets. They found that an enzyme called MELK was higher in chronic ITP than in newly diagnosed ITP, and higher in newly diagnosed patients than in those in remission.
To confirm these findings, the team examined bone marrow samples from 11 newly diagnosed ITP patients and 10 healthy donors. MELK expression in bone marrow megakaryocytes was significantly higher in ITP patients than in healthy donors; those with higher MELK expression had lower platelet counts.
When the researchers exposed megakaryocytes derived from human stem cells to blood collected from ITP patients, MELK expression increased, along with TNF-alpha, a proinflammatory signaling protein.
Blocking MELK activity with two distinct molecules increased levels of markers reflecting megakaryocyte maturation. MELK-inhibited cells also grew larger and increased in the proportion of so-called high-ploidy megakaryocytes — cells containing 16 or more copies of their DNA — which are the main platelet-producing cells.
The final stage of megakaryocyte maturation involves the cell extending long, branching projections called proplatelets, from which platelets are ultimately released, a process called proplatelet formation (PPF).
Under microscopy, MELK inhibitors were shown to promote PPF, including the formation of characteristic finger-like projections and bead-like structures. Likewise, the proportion of megakaryocytes undergoing PPF increased with MELK inhibitor treatment compared with controls. Platelet production also increased significantly after MELK inhibition.
Researchers tested their findings in mouse models of ITP
In a passive ITP mouse model, in which a low platelet count was induced by an antibody against a platelet surface protein, mice treated with an MELK inhibitor showed faster platelet recovery. Cell analysis and tissue staining confirmed higher numbers of mature bone marrow megakaryocytes in treated mice.
Given the limitations of a passive ITP mouse model, the team created an active ITP mouse model in which immune cells from immunized donor mice were transferred into recipient mice to trigger immune-mediated platelet destruction.
Treatment with the MELK inhibitor did not affect platelet lifespan but significantly accelerated platelet recovery, with treated mice reaching higher platelet counts by day 14 than controls. Consistently, bone marrow tissue showed increased numbers of megakaryocytes in treated mice.
In final mechanistic studies, MELK was found to act like a brake on platelet production. Conversely, reduced MELK activity activated the MAPK/ERK growth pathway and altered the cell’s structure, thereby helping to produce more platelets.
“This study reveals that MELK inhibition promotes [megakaryocyte] maturation and platelet production, an effect associated with activation of the MAPK/ERK signaling pathway,” the team concluded. “These findings provide insights into ITP [development] and highlight MELK as a potential therapeutic target.”
