Mirabile Margherita, Tombari Camilla, Neroni Anita, Tavernari Lara, Norfo Ruggiero, Bianchi Elisa, Maccaferri Monica, Mora Barbara, Parenti Sandra, Carretta Chiara, Bertesi Matteo, Malerba Marica, Papa Elisa, Fabbiani Luca, Bartalucci Niccolò, Guglielmelli Paola, Potenza Leonardo, Losi Lorena, Passamonti Francesco, Tagliafico Enrico, Luppi Mario, Rontauroli Sebastiano, Vannucchi Alessandro Maria, Manfredini Rossella
Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
J Cell Mol Med. 2025 Jul;29(14):e70720. doi: 10.1111/jcmm.70720.
Extramedullary haematopoiesis (EMH) refers to blood generation outside of the bone marrow (BM). In Myelofibrosis (MF), a myeloproliferative neoplasm, the disruption of BM microenvironment promotes haematopoietic stem and progenitor cells (HSPCs) mobilisation, resulting in the onset of EMH in the spleen, and then in splenomegaly. Although JAK2 inhibitors have a good efficacy in reducing splenomegaly, the presence of a significant proportion of non-responder patients underlines the need to explore the cellular mechanisms responsible for the EMH onset. In a MF mouse model, Ruxolitinib induces a reduction in spleen volume but does not affect EMH. CD44 inhibition successfully reduces monocyte and HSPC migration in an in vitro extravasation model. Strikingly, MF monocytes are more effective in promoting HSPC migration through the production of hyaluronic acid. Collectively, our results demonstrate that CD44 regulates the migration of monocytes that are crucial for the onset of EMH in MF patients, as they produce CD44 ligands recruiting HSPCs from the BM.
髓外造血（EMH）是指在骨髓（BM）之外产生血液。在骨髓增殖性肿瘤骨髓纤维化（MF）中，骨髓微环境的破坏促进了造血干细胞和祖细胞（HSPCs）的动员，导致脾脏出现EMH，进而导致脾肿大。尽管JAK2抑制剂在减轻脾肿大方面有良好疗效，但相当一部分无反应患者的存在凸显了探索EMH发病机制的必要性。在一个MF小鼠模型中，鲁索替尼可使脾脏体积减小，但不影响EMH。在体外渗出模型中，抑制CD44可成功减少单核细胞和HSPCs的迁移。引人注目的是，MF单核细胞通过产生透明质酸，在促进HSPCs迁移方面更有效。总体而言，我们的结果表明，CD44调节单核细胞的迁移，而单核细胞对于MF患者EMH的发病至关重要，因为它们产生招募BM中HSPCs的CD44配体。
