Regional
Circular RNA circFUT8 uncovered as master regulator of platelet production
Platelet transfusion is an effective treatment for thrombocytopenia, but donor-derived platelets are insufficient to meet the demand. Ex vivo generated platelets offer a potential solution, but the mechanisms of megakaryopoiesis and platelet production are not fully understood. In the recent issue of Blood, Wu et al. found circFUT8 stabilizes TNS1 mRNA via IGF2BP2 to promotes proplatelet formation.
Transfusion of platelet products from healthy donors constitutes a critical, often irreplaceable therapeutic intervention for critically ill patients. However, platelet supplies rely exclusively on volunteer donations, which struggle to meet escalating clinical demand. Recent data indicate that platelet requirements continue to rise even as red blood cell and plasma usage declines. According to the U.S. National Blood Collection and Utilization Survey, clinical demand for platelets increased by 16% between 2017 and 2019, while collection decreased by 2%. Recent investigations into the regulatory mechanisms of platelet production offer new strategies to address this supply-demand imbalance. Wu et al. identified circFUT8 as a critical promoter of proplatelet formation (PPF), demonstrating that it interacts with IGF2BP2 to stabilize TNS1 mRNA, thereby modulating actin cytoskeleton dynamics.
Recent advances have illuminated the mechanisms underlying proplatelet formation and release. For instance, casein kinase 1α (CK1α) regulates cytoskeletal dynamics to influence proplatelet formation, while miR-125a-5p serves as a positive regulator by modulating the actin-bundling protein L-plastin (LCP1). Our study demonstrates that circFUT8 interacts with the RNA-binding protein IGF2BP2 to stabilize TNS1 mRNA, which encodes a regulator of actin dynamics, in an m6A-dependent manner, thereby promoting proplatelet formation. These findings address a critical knowledge gap regarding the functional roles of circRNAs and RNA modifications in platelet biogenesis and establish a novel paradigm for investigating circRNA mechanisms in platelet physiology and pathology.
Dysregulated platelet production underlies hematologic disorders such as thrombocytopenia. Thrombopoietin (TPO) and its receptor represent key therapeutic targets for managing this condition. Recombinant human TPO (rhTPO) is clinically employed to effectively mitigate thrombocytopenia resulting from myelosuppression induced by chemotherapy or radiotherapy. To overcome limitations in administration route and duration of efficacy associated with rhTPO, several TPO receptor agonists have been developed, including eltrombopag, avatrombopag, lusutrombopag, and romiplostim. These agents are used to treat immune thrombocytopenia (ITP) and thrombocytopenia secondary to other conditions. Moreover, exploration of TPO-independent mechanisms of platelet production may yield alternative therapeutic strategies. The circFUT8-IGF2BP2-TNS1 axis identified in our study represents a potential target for future development of alternative thrombocytopenia therapies.
Large-scale ex vivo production of functional platelets offers a promising strategy to address clinical supply shortages. Recent advances have optimized donor cell sources, including CD34+ hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells, while refining the thrombopoietic microenvironment through improved culture conditions and three-dimensional scaffold systems. Transcriptomic sequencing, single-cell analysis, bioinformatics, and advanced microscopy have collectively elucidated key aspects of megakaryocyte biology, particularly the mechanisms governing platelet release from mature megakaryocytes. Emerging evidence highlights the critical roles of post-transcriptional regulation and metabolic reprogramming in megakaryocyte maturation and platelet biogenesis. These mechanistic insights establish a robust theoretical framework for in vitro platelet generation. Ongoing investigations continue to decipher the molecular details of thrombopoiesis, providing novel strategies to enhance both the efficiency and yield of ex vivo platelet production.
References
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