文章：

间充质基质细胞中的Neuropilin2：骨髓纤维化中潜在的新型治疗靶点

Neuropilin2 in Mesenchymal Stromal Cells as a Potential Novel Therapeutic Target in Myelofibrosis

原文发布日期：18 May 2024

DOI: 10.3390/cancers16101924

类型: Article

开放获取: 是

英文摘要：

Bone marrow fibrosis in myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML) is associated with poor prognosis and early treatment failure. Myelofibrosis (MF) is accompanied by reprogramming of multipotent bone marrow mesenchymal stromal cells (MSC) into osteoid and fiber-producing stromal cells. We demonstrate NRP2 and osteolineage marker NCAM1 (neural cell adhesion molecule 1) expression within the endosteal niche in normal bone marrow and aberrantly in MPN, MDS MPN/MDS overlap syndromes and AML (n= 99), as assessed by immunohistochemistry. Increased and diffuse expression in mesenchymal stromal cells and osteoblasts correlates with high MF grade in MPN (p< 0.05 for NRP2 and NCAM1). Single cell RNA sequencing (scRNAseq) re-analysis demonstrated NRP2 expression in endothelial cells and partial co-expression of NRP2 and NCAM1 in normal MSC and osteoblasts. Potential ligands included transforming growth factor β1 (TGFB1) from osteoblasts and megakaryocytes. Murine ThPO and JAK2V617Fmyelofibrosis models showed co-expression of Nrp2 and Ncam1 in osteolineage cells, while fibrosis-promoting MSC only express Nrp2. In vitro experiments with MC3T3-E1 pre-osteoblasts and analysis ofNrp2−/−mouse femurs suggest that Nrp2 is functionally involved in osteogenesis. In summary, NRP2 represents a potential novel druggable target in patients with myelofibrosis.

摘要翻译： 

骨髓纤维化在骨髓增殖性肿瘤（MPN）、骨髓增生异常综合征（MDS）、MPN/MDS重叠综合征及急性髓系白血病（AML）中与不良预后及早期治疗失败相关。骨髓纤维化（MF）伴随多能骨髓间充质基质细胞（MSC）重编程为类骨质及纤维生成基质细胞。通过免疫组化检测，我们在正常骨髓骨内膜微环境及MPN、MDS、MPN/MDS重叠综合征与AML（n=99）异常样本中证实了NRP2与成骨谱系标志物NCAM1（神经细胞黏附分子1）的表达。间充质基质细胞与成骨细胞中NRP2与NCAM1表达量的增加及弥散分布与MPN患者的高MF分级相关（p<0.05）。单细胞RNA测序（scRNAseq）再分析显示内皮细胞表达NRP2，正常MSC与成骨细胞中部分共表达NRP2与NCAM1。潜在配体包括源自成骨细胞与巨核细胞的转化生长因子β1（TGFB1）。小鼠ThPO与JAK2V617F骨髓纤维化模型显示成骨谱系细胞共表达Nrp2与Ncam1，而促纤维化MSC仅表达Nrp2。通过MC3T3-E1前成骨细胞体外实验及Nrp2−/−小鼠股骨分析，提示Nrp2在功能上参与成骨过程。综上，NRP2可作为骨髓纤维化患者潜在的新型药物靶点。

原文链接：

Neuropilin2 in Mesenchymal Stromal Cells as a Potential Novel Therapeutic Target in Myelofibrosis