Wojtowicz Edyta E, Lechman Eric R, Hermans Karin G, Schoof Erwin M, Wienholds Erno, Isserlin Ruth, van Veelen Peter A, Broekhuis Mathilde J C, Janssen George M C, Trotman-Grant Aaron, Dobson Stephanie M, Krivdova Gabriela, Elzinga Jantje, Kennedy James, Gan Olga I, Sinha Ankit, Ignatchenko Vladimir, Kislinger Thomas, Dethmers-Ausema Bertien, Weersing Ellen, Alemdehy Mir Farshid, de Looper Hans W J, Bader Gary D, Ritsema Martha, Erkeland Stefan J, Bystrykh Leonid V, Dick John E, de Haan Gerald
Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Cell Stem Cell. 2016 Sep 1;19(3):383-96. doi: 10.1016/j.stem.2016.06.008. Epub 2016 Jul 14.
Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve therapeutic outcome, available protocols and the molecular mechanisms governing the self-renewal of HSCs are unclear. Here, we show that ectopic expression of a single microRNA (miRNA), miR-125a, in purified murine and human multipotent progenitors (MPPs) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and western blot analysis, we identified a restricted set of miR-125a targets involved in conferring long-term repopulating capacity to MPPs in humans and mice. Our findings offer the innovative potential to use MPPs with enhanced self-renewal activity to augment limited sources of HSCs to improve clinical protocols.
脐带血（CB）是用于异基因干细胞移植的造血干细胞（HSCs）的一种便捷且广泛使用的来源。然而，造血干细胞数量有限仍然是其临床应用的主要限制因素。虽然一种可行的选择是扩增造血干细胞以改善治疗效果，但现有的方案以及控制造血干细胞自我更新的分子机制尚不清楚。在此，我们表明，在纯化的小鼠和人类多能祖细胞（MPPs）中异位表达单个微小RNA（miRNA），即miR-125a，可导致移植受体小鼠的自我更新增加和强大的长期多谱系重建。通过定量蛋白质组学和蛋白质印迹分析，我们确定了一组有限的miR-125a靶标，这些靶标赋予人类和小鼠的多能祖细胞长期重建能力。我们的研究结果提供了创新潜力，即使用具有增强自我更新活性的多能祖细胞来增加有限的造血干细胞来源，以改进临床方案。
