巨核细胞
造血
骨髓
细胞生物学
血小板生成素
祖细胞
化学
血小板因子4
血小板
糖胺聚糖
干细胞
免疫学
生物
生物化学
作者
Joshua Lykins,Isabelle C. Becker,Virginia Camacho,Hammodah R. Alfar,JoonWoo Park,Joseph E. Italiano,Sidney W. Whiteheart
出处
期刊:Blood Advances
[American Society of Hematology]
日期:2024-06-28
标识
DOI:10.1182/bloodadvances.2024012995
摘要
Megakaryocytes (MKs) produce platelets, and like other hematopoietic progenitors they are involved in homeostatic aspects of their bone marrow niche. MKs release and endocytose various factors, such as platelet factor 4 (PF4/CXCL4). Here we show that the intra-α-granular proteoglycan, serglycin (SRGN) plays a key role in this process by retaining PF4 and perhaps other factors during MK maturation. Immature, SRGN-/- MKs released ~80% of their PF4 and conditioned media from these cells negatively affected wild-type MK differentiation in vitro. This was replicated in wild-type MKs, by treatment with the polycation surfen, a known inhibitor of glycosaminoglycan/protein interactions. In vivo, SRGN-/- mice had an interstitial accumulation of PF4, TGFβ-1, IL-1β, and TNF-α in their bone marrow and increased numbers of immature MKs, consistent with their mild thrombocytopenia. SRGN-/- mice also had reduced numbers of hematopoietic stem cells and multipotent progenitors, reduced laminin, and increased collagen I deposition. These findings demonstrate that MKs depend on SRGN and its charged glycosaminoglycans to balance the distribution of PF4 and perhaps other factors between their α-granules and their adjacent extracellular spaces. Disrupting this balance negatively affects MK development and bone marrow microenvironment homeostasis.
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