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1166 CircFUT8 Promotes Megakaryocyte Proplatelet Formation By Regulating Actin Cytoskeleton Reorganization

Program: Oral and Poster Abstracts
Session: 301. Platelets and Megakaryocytes: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Huang Wu, Ph.D1*, Yao Lu1*, Denglian Sun1*, Huayu Lin, Ph.D2*, Wenjun Xia1*, Ruichi Chen1*, Jun Chen1*, Jiaying Xie1*, Rong Feng1*, Lijie Ren1*, Zeqing Miao1*, Junling Liu, Ph.D3*, Yang Yu, M.D. & Ph.D2* and Aiqing Wen, M.D. & Ph.D1*

1Department of Blood Transfusion, Daping Hosptial of Army Medical University, Chongqing, China
2Department of Transfusion Medicine, First Medical Center of Chinese PLA General Hospital, Beijing, China
3Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Megakaryocytes (MKs) are large cells derived from hematopoietic stem cells (HSCs) through a process of differentiation and maturation. Mature MKs extend long processes called proplatelets, which are released into bone marrow sinusoids under the shear forces of blood flow. These proplatelets also form platelets in the lungs. Platelets are small cell fragments that play crucial roles in hemostasis, thrombosis, and immunity. The process of platelet generation from megakaryocytes is intricately orchestrated by non-coding RNAs, such as miRNAs. Another non-coding RNA, circRNA, is highly abundant in platelets, but its role in platelet production remains unclear. We performed RNA-seq and bioinformatics analysis to identify circRNAs during the differentiation of megakaryocytes from umbilical cord blood hematopoietic stem cells. We found that circFUT8, a novel circRNA, increases with megakaryocyte differentiation and is enriched in mature megakaryocytes. Knockdown and overexpression studies showed that circFUT8 promotes human megakaryocyte proplatelet formation (PPF) in vitro. We also found that circFUT8 is highly conserved between humans and mice. In vitro, knockdown of circFUT8 decreases mouse megakaryocyte PPF. In vivo, it reduces murine platelet counts, prolongs tail bleeding time, and reduces the number of MKs in contact with sinusoids. Furthermore, knockdown of circFUT8 reduces F-actin polymerization and impairs spreading on collagen. Additionally, we revealed that circFUT8 interacts with insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and stabilizes tensin 1 (TNS1) mRNA. We observed that knockdown of TNS1 disrupts the actin cytoskeleton and decreases PPF. Our study highlights the crucial functions of circRNAs in platelet production and the rearrangement of the actin cytoskeleton.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH