Kupffer cells are essential for platelet- mediated thrombopoietin generation in the liver

• 成果类型: Article
• 署名作者: Karakas, Danielle; Li, June; Ma, Wenjing; Wu, Xun Grace; Khoury, Christopher J.; Masoud, Mina; Hoard, Brock; Liu, Yuning Jay; Zhu, Guangheng; Chen, Junmei; Sim, Martha; Shen, Chuanbin; MacParland, Sonya A.; Lopez, Jose A.; Kahr, Walter H. A.; Ni, Heyu
• 署名单位: University of Toronto; University of Toronto; Saint Michaels Hospital Toronto; University of Toronto; Canadian Blood Services; University of Washington; University of Washington Seattle; Ocean University of China; University of Toronto; University Health Network Toronto; University of Toronto; University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8682
• DOI: 10.1073/pnas.2517319122
• 发表日期: 2025-09-23
• 关键词: intravenous immunoglobulin-g; c-mpl; immune thrombocytopenia; antiplatelet gpiibiiia; megakaryocyte growth; relative efficacy; aplastic-anemia; receptor; identification; mechanisms

摘要

Thrombopoietin (TPO), predominantly produced by the liver, is the key regulator for platelet production and the hematopoietic stem cell niche. Our earlier report demonstrated that platelet GPIb alpha is required for hepatocellular TPO generation, which is the major resource of TPO in the blood circulation. However, how hepatocytes physically contact circulating sinusoidal platelets across the liver endothelium for this process is unknown. Kupffer cells reside in contact with both sinusoidal blood and underlying hepatocytes, and mediate senescent platelet clearance, but their role in TPO regulation has never been explored. Here, we found Kupffer cell depletion via either clodronate liposomes or specific transgenic models abrogated circulating TPO. Kupffer cell depletion also prevented TPO level increase in GPIb alpha- deficient mice following wild-type (GPIb alpha+) platelet transfusion, signifying an interdependent mechanism for TPO regulation. Mice treated with arsenite had significantly decreased liver endothelial fenestrations and hepatocyte sinusoidal protrusions as well as TPO levels. This effect was exacerbated by Kupffer cell depletion, and Kupffer cells were identified to enhance liver endothelial fenestrations. Electron microscopy and immunofluorescence analysis of the liver revealed platelets arrested on Kupffer cell surface were in contact with hepatocyte protrusions. Thus, we elucidated that Kupffer cells promote endothelial fenestrae and hepatocyte protrusions, accumulate circulating platelets, and facilitate cellular interactions between hepatocytes and platelets, which drive TPO generation. This connection between platelet clearance and thrombopoiesis should have broad implications for hematology and pathologies such as Bernard-Soulier syndrome, thrombocytopenias, as well as liver diseases.