Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
Cell Stem Cell. 2013 Sep 5;13(3):285-99. doi: 10.1016/j.stem.2013.06.009. Epub 2013 Jul 11.
Multipotent stromal cells (MSCs) and their osteoblastic lineage cell (OBC) derivatives are part of the bone marrow (BM) niche and contribute to hematopoietic stem cell (HSC) maintenance. Here, we show that myeloproliferative neoplasia (MPN) progressively remodels the endosteal BM niche into a self-reinforcing leukemic niche that impairs normal hematopoiesis, favors leukemic stem cell (LSC) function, and contributes to BM fibrosis. We show that leukemic myeloid cells stimulate MSCs to overproduce functionally altered OBCs, which accumulate in the BM cavity as inflammatory myelofibrotic cells. We identify roles for thrombopoietin, CCL3, and direct cell-cell interactions in driving OBC expansion, and for changes in TGF-β, Notch, and inflammatory signaling in OBC remodeling. MPN-expanded OBCs, in turn, exhibit decreased expression of many HSC retention factors and severely compromised ability to maintain normal HSCs, but effectively support LSCs. Targeting this pathological interplay could represent a novel avenue for treatment of MPN-affected patients and prevention of myelofibrosis.
多能基质细胞 (MSCs) 和其成骨细胞系细胞 (OBC) 衍生物是骨髓 (BM) 龛的一部分，并有助于造血干细胞 (HSC) 的维持。在这里，我们表明骨髓增殖性肿瘤 (MPN) 逐渐重塑骨内膜 BM 龛成为自我强化的白血病龛，损害正常造血，有利于白血病干细胞 (LSC) 功能，并导致 BM 纤维化。我们表明，白血病髓系细胞刺激 MSCs 过度产生功能改变的 OBC，这些 OBC 作为炎症性骨髓纤维化细胞在 BM 腔中积累。我们确定了血小板生成素、CCL3 和直接细胞-细胞相互作用在驱动 OBC 扩增中的作用，以及 TGF-β、Notch 和炎症信号在 OBC 重塑中的变化。反过来，MPN 扩增的 OBC 表现出许多 HSC 保留因子的表达降低，严重损害维持正常 HSC 的能力，但能有效地支持 LSC。靶向这种病理性相互作用可能为治疗 MPN 患者和预防骨髓纤维化提供新的途径。
