Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, The Catholic University of Korea, College of Medicine, Seoul, 137-701, Korea.
Department of Medical Lifescience, The Catholic University of Korea, College of Medicine, Seoul, 137-701, Korea.
Sci Rep. 2019 Jan 30;9(1):1007. doi: 10.1038/s41598-018-36999-5.
The bone marrow (BM) microenvironment serves as a stem cell niche regulating the in vivo cell fate of normal hematopoietic stem cells (HSC) as well as leukemia stem cells (LSCs). Accumulating studies have indicated that the regeneration of normal HSCs and the process of leukemogenesis change with advancing age. However, the role of microenvironmental factors in these age-related effects are unclear. Here, we compared the stem cell niche in neonatal and adult BM to investigate potential differences in their microenvironmental regulation of both normal and leukemic stem cells. We found that the mesenchymal niche in neonatal BM, compared to adult BM, was characterized by a higher frequency of primitive subsets of mesenchymal stroma expressing both platelet-derived growth factor receptor and Sca-1, and higher expression levels of the niche cross-talk molecules, Jagged-1 and CXCL-12. Accordingly, normal HSCs transplanted into neonatal mice exhibited higher levels of regeneration in BM, with no difference in homing efficiency or splenic engraftment compared to adult BM. In contrast, in vivo self-renewal of LSCs was higher in adult BM than in neonatal BM, with increased frequencies of leukemia-initiating cells as well as higher lympho-myeloid differentiation potential towards biphenotypic leukemic cells. These differences in LSC self-renewal capacity between neonates and adults was abrogated by switching of recipients, confirming their microenvironmental origin. Our study provides insight into the differences in leukemic diseases observed in childhood and adults, and is important for interpretation of many transplantation studies involving neonatal animal models.
骨髓（BM）微环境作为干细胞龛，调节正常造血干细胞（HSC）和白血病干细胞（LSC）的体内细胞命运。越来越多的研究表明，正常 HSC 的再生和白血病发生过程随年龄增长而变化。然而，微环境因素在这些与年龄相关的效应中的作用尚不清楚。在这里，我们比较了新生儿和成人 BM 中的干细胞龛，以研究它们对正常和白血病干细胞的微环境调节的潜在差异。我们发现，与成人 BM 相比，新生儿 BM 中的间充质龛以表达血小板衍生生长因子受体和 Sca-1 的原始间充质基质亚群的更高频率为特征，并且间充质龛细胞间交流分子 Jagged-1 和 CXCL-12 的表达水平更高。相应地，移植到新生儿小鼠中的正常 HSC 在 BM 中表现出更高水平的再生，与成人 BM 相比，归巢效率或脾脏植入没有差异。相比之下，LSC 在体内的自我更新在成人 BM 中高于新生儿 BM，具有更高频率的白血病起始细胞，以及向双表型白血病细胞的更高淋巴髓样分化潜力。接受者之间的切换消除了 LSC 自我更新能力在新生儿和成人之间的差异，证实了它们的微环境起源。我们的研究深入了解了儿童和成人中观察到的白血病疾病的差异，对于解释涉及新生儿动物模型的许多移植研究非常重要。
