Graduate Program in Molecular & Cellular Pharmacology, Stony Brook University, Stony Brook, NY, USA.
New York Institute of Technology College of Osteopathic Medicine, Glen Head, NY, USA.
Stem Cells. 2022 Apr 29;40(4):359-370. doi: 10.1093/stmcls/sxac005.
Megakaryocytes (MKs) is an important component of the hematopoietic niche. Abnormal MK hyperplasia is a hallmark feature of myeloproliferative neoplasms (MPNs). The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs. Using a murine model of MPN in which the human JAK2V617F gene is expressed in the MK lineage, we show that the JAK2V617F-bearing MKs promote hematopoietic stem cell (HSC) aging, manifesting as myeloid-skewed hematopoiesis with an expansion of CD41+ HSCs, a reduced engraftment and self-renewal capacity, and a reduced differentiation capacity. HSCs from 2-year-old mice with JAK2V617F-bearing MKs were more proliferative and less quiescent than HSCs from age-matched control mice. Examination of the marrow hematopoietic niche reveals that the JAK2V617F-bearing MKs not only have decreased direct interactions with hematopoietic stem/progenitor cells during aging but also suppress the vascular niche function during aging. Unbiased RNA expression profiling reveals that HSC aging has a profound effect on MK transcriptomic profiles, while targeted cytokine array shows that the JAK2V617F-bearing MKs can alter the hematopoietic niche through increased levels of pro-inflammatory and anti-angiogenic factors. Therefore, as a hematopoietic niche cell, MKs represent an important connection between the extrinsic and intrinsic mechanisms for HSC aging.
巨核细胞（MKs）是造血龛的重要组成部分。异常 MK 增生是骨髓增殖性肿瘤（MPNs）的标志特征。JAK2V617F 突变存在于大多数 MPN 患者的造血细胞中。使用 JAK2V617F 在 MK 谱系中表达的 MPN 小鼠模型，我们表明携带 JAK2V617F 的 MK 促进造血干细胞（HSC）衰老，表现为髓系偏向性造血，CD41+HSCs 扩增，植入和自我更新能力降低，分化能力降低。来自携带 JAK2V617F 的 MK 的 2 岁小鼠的 HSCs 比来自年龄匹配的对照小鼠的 HSCs 具有更高的增殖能力和更低的静止性。对骨髓造血龛的检查表明，携带 JAK2V617F 的 MK 不仅在衰老过程中与造血干细胞/祖细胞的直接相互作用减少，而且在衰老过程中还抑制血管龛功能。无偏 RNA 表达谱分析表明，HSC 衰老对 MK 转录组谱有深远影响，而靶向细胞因子阵列显示，携带 JAK2V617F 的 MK 可以通过增加促炎和抗血管生成因子的水平来改变造血龛。因此，作为造血龛细胞，MK 代表了 HSC 衰老的内在和外在机制之间的重要联系。
