期刊
STEM CELLS
卷 40, 期 4, 页码 359-370出版社
OXFORD UNIV PRESS
DOI: 10.1093/stmcls/sxac005
关键词
megakaryocyte; microenvironment; hematopoietic stem cells; Janus kinase; aging
资金
- National Heart, Lung, and Blood Institute [NIH R01 HL134970]
- VA Career Development Award [BX001559]
- VA Merit Award [BX003947]
The presence of JAK2V617F mutation in MKs has been shown to promote HSC aging and alter the hematopoietic niche. This leads to abnormal hematopoiesis and reduced HSC functionality. Furthermore, JAK2V617F-bearing MKs can modulate the hematopoietic niche through changes in cytokine levels.
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.
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