Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, The Catholic University of Korea, College of Medicine, Seoul, South Korea.
Department of Medical Lifescience, The Catholic University of Korea, College of Medicine, Seoul, South Korea.
Stem Cells. 2018 Oct;36(10):1617-1629. doi: 10.1002/stem.2870. Epub 2018 Jul 31.
Accumulating studies have shown the cellular nature of hematopoietic stem cell (HSC) niche in bone marrow (BM) and their degenerative changes under leukemic conditions. However, the dynamic adaptation of niche cells to changes in physiological stimulatory signals remains largely uncharacterized. Here, we have established a niche stimulation model induced by 5-fluorouracil. This model reveals a rapid and reversible conversion of mesenchymal cells into niche-like stromal cells, which exhibit a platelet-derived growth factor receptor-alpha /leptin receptor (PL) phenotype. These cells selectively induce the niche signaling molecule, Jagged-1, but not CXCL12, to initiate a stimulation-induced regeneration of HSCs in a Jagged-1 dependent manner. Conversion of mesenchymal cells into niche-like cells occurred independently of mitotic activation. The conversion was accompanied by the acquisition of primitive mesenchymal cell characteristics, including the rapid induction of stage specific embryonic antigen-3 and the acquisition of clonogenic potential. The stimulation-induced remodeling of the BM niche resulted in a positive stimulatory effect on the regeneration of normal HSC, but exerted inhibitory effects on leukemic cells, leading to a competitive advantage for normal HSCs in the BM niche and prolonged survival of mice engrafted with leukemic cells. Thus, the reactive conversion of mesenchymal stroma into niche-like cells reveals the adaptive changes of the BM microenvironment to stimuli, and provides insight on the remodeling of niche toward pronormal/antileukemic microenvironment, which can counteract the progressive proleukemic changes driven by the leukemic niche. Our study raises the potential for antileukemic niche targeting therapy. Stem Cells 2018;36:1617-1629.
越来越多的研究表明，骨髓（BM）中造血干细胞（HSC）龛的细胞特性及其在白血病条件下的退行性变化。然而，龛细胞对生理刺激信号变化的动态适应在很大程度上仍未被描述。在这里，我们建立了一个由 5-氟尿嘧啶诱导的龛刺激模型。该模型揭示了间充质细胞快速且可逆地转化为龛样基质细胞，表现出血小板衍生生长因子受体-α/瘦素受体（PL）表型。这些细胞选择性地诱导龛信号分子 Jagged-1，但不诱导 CXCL12，以 Jagged-1 依赖的方式启动 HSC 的刺激诱导再生。间充质细胞向龛样细胞的转化与有丝分裂激活无关。转化伴随着原始间充质细胞特征的获得，包括快速诱导阶段特异性胚胎抗原-3 和获得克隆形成潜力。BM 龛的刺激诱导重塑导致对正常 HSC 再生的正向刺激作用，但对白血病细胞施加抑制作用，导致正常 HSCs 在 BM 龛中具有竞争优势，并延长植入白血病细胞的小鼠的存活时间。因此，间充质基质的反应性转化揭示了 BM 微环境对刺激的适应性变化，并提供了对龛向正常/抗白血病微环境重塑的深入了解，这可以对抗由白血病龛驱动的进行性白血病变化。我们的研究提出了针对抗白血病龛的靶向治疗的潜力。干细胞 2018;36:1617-1629。
