紫杉醇能在缺乏血小板生成素受体(Mpl)的情况下改善血栓形成。

IF 5.5 2区 医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2024-09-20 DOI:10.1016/j.jtha.2024.08.025
Panpan Meng, Wenyu Liu, Jiawen Lao, Xunwei Liu, Yangping Zhang, Ying Sun, Riyang Zhou, Changhong Du, Junping Wang, Dejian Zhao, Qing Lin, Yiyue Zhang
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引用次数: 0

摘要

背景:血小板对血栓形成和止血至关重要:血小板对血栓形成和止血至关重要。TPO-MPL 途径是生成血小板的主要途径。血小板生成失调会导致血小板形成和/或功能相关性疾病,如血小板减少症。紫杉醇是一种广泛使用的化疗药物,可能与血小板有关,但紫杉醇对血小板生成的影响值得全面探讨:我们的研究重点是确定调节血小板生成的因素,阐明紫杉醇对血小板生成的调节机制,尤其是发现绕过 TPO-MPL 的途径:我们使用 Tg(mpl:eGFP) 斑马鱼体内模型进行了药物筛选,以确定 FDA 批准的能够促进血小板生成的化合物。损伤实验用于评估血小板功能。进行了 BrdU、TUNEL 和 RNA-Seq 分析,以探索细胞学和分子机制。常规血液检测和流式细胞术用于分析小鼠表型:结果:我们发现紫杉醇能够通过加速斑马鱼血小板系细胞的增殖来扩增血小板,并提高小鼠的血小板水平。这种效应是绕过血小板生成素受体(Mpl)产生的。我们发现,紫杉醇促进血小板生成可能涉及 JAK2-ERK1/2 MAPK 信号级联,这是 MPL 和其他调节因子不可或缺的途径。我们的研究结果进一步证明,在紫杉醇诱导的血栓形成过程中,ERK1/2至少部分处于JAK2的下游:结论:紫杉醇可绕过 Mpl 但可能通过 Jak2-Erk1/2 MAPK 通路促进血栓形成。结论:紫杉醇可通过绕过Mpl,但推测是通过Jak2-Erk1/2 MAPK通路促进血小板生成,这将有助于临床上理解紫杉醇与血小板之间的关系,紫杉醇在相关疾病中可能具有保护血小板和改善血小板增多的潜在价值。
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Paclitaxel improves thrombopoiesis in the absence of thrombopoietin receptor (Mpl).

Background: Platelets are critical for thrombosis and hemostasis. The THPO-MPL pathway is the primary pathway for generating thrombocytes. Dysregulation of thrombopoiesis results in platelet formation and/or function-related disorders, such as thrombocytopenia. Paclitaxel is an extensively utilized chemotherapeutic agent and its activity may be related to platelets, but the effect of paclitaxel on thrombocytopoiesis warrants comprehensive exploration.

Objectives: We focused on identifying factors that regulate thrombocyte production and elucidating paclitaxel's regulatory mechanisms on thrombocytopoiesis, with a particular emphasis on discovering mechanisms that bypass THPO-MPL pathways.

Methods: We performed drug screenings using the Tg(mpl:eGFP) zebrafish model in vivo to identify Food and Drug Administration-approved compounds capable of boosting thrombocyte production. An injury experiment was used to evaluate thrombocyte function. Bromodeoxyuridine assays, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and RNA sequencing analyses were performed to explore cytological and molecular mechanisms. Routine blood testing and flow cytometry were used to analyze mouse phenotypes.

Results: We found that paclitaxel expands thrombocytes by accelerating the proliferation of thrombocytic lineage cells in zebrafish and elevates platelet levels in mice. This effect occurs by bypassing the thrombopoietin receptor (Mpl). We found that paclitaxel promotes thrombopoiesis, potentially involving the JAK2-ERK1/2 MAPK signaling cascade, a pathway integral to MPL and other regulators. Our results further demonstrate that ERK1/2 is at least partially downstream of JAK2 in paclitaxel-induced thrombopoiesis.

Conclusion: Paclitaxel could promote thrombopoiesis by bypassing Mpl but presumably via the JAK2-ERK1/2 MAPK pathways. It will aid in understanding the relationship between paclitaxel and platelets clinically, and paclitaxel may have potential value for safeguarding platelets and improving thrombocytosis in related diseases.

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来源期刊
Journal of Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis 医学-外周血管病
CiteScore
24.30
自引率
3.80%
发文量
321
审稿时长
1 months
期刊介绍: The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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