Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
Research Unit Stem Cell Dynamics, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.
Nature. 2019 Sep;573(7774):426-429. doi: 10.1038/s41586-019-1531-6. Epub 2019 Sep 4.
Haematopoietic stem cells self-renew and differentiate into all blood lineages throughout life, and can repair damaged blood systems upon transplantation. Asymmetric cell division has previously been suspected to be a regulator of haematopoietic-stem-cell fate, but its existence has not directly been shown. In asymmetric cell division, asymmetric fates of future daughter cells are prospectively determined by a mechanism that is linked to mitosis. This can be mediated by asymmetric inheritance of cell-extrinsic niche signals by, for example, orienting the divisional plane, or by the asymmetric inheritance of cell-intrinsic fate determinants. Observations of asymmetric inheritance or of asymmetric daughter-cell fates alone are not sufficient to demonstrate asymmetric cell division. In both cases, sister-cell fates could be controlled by mechanisms that are independent of division. Here we demonstrate that the cellular degradative machinery-including lysosomes, autophagosomes, mitophagosomes and the protein NUMB-can be asymmetrically inherited into haematopoietic-stem-cell daughter cells. This asymmetric inheritance predicts the asymmetric future metabolic and translational activation and fates of haematopoietic-stem-cell daughter cells and their offspring. Therefore, our studies provide evidence for the existence of asymmetric cell division in haematopoietic stem cells.
造血干细胞在整个生命周期中自我更新并分化为所有血液谱系，并且可以在移植后修复受损的血液系统。不对称细胞分裂先前被怀疑是造血干细胞命运的调节剂，但它的存在尚未直接证明。在不对称细胞分裂中，未来子细胞的不对称命运通过与有丝分裂相关的机制被预先确定。这可以通过细胞外在龛位信号的不对称遗传来介导，例如通过定向分裂平面，或者通过细胞内在命运决定因素的不对称遗传来介导。仅观察不对称遗传或不对称子细胞命运不足以证明不对称细胞分裂。在这两种情况下，姐妹细胞命运都可以通过独立于分裂的机制来控制。在这里，我们证明包括溶酶体、自噬体、线粒体自噬体和蛋白质 NUMB 在内的细胞降解机制可以不对称地遗传到造血干细胞的子细胞中。这种不对称遗传预测了造血干细胞子细胞及其后代的未来代谢和翻译激活以及命运的不对称性。因此，我们的研究为造血干细胞中存在不对称细胞分裂提供了证据。
