Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Ulm, Germany.
Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
PLoS Biol. 2018 Sep 20;16(9):e2003389. doi: 10.1371/journal.pbio.2003389. eCollection 2018 Sep.
Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase cell division control protein 42 (Cdc42). Here we demonstrate-using a comprehensive set of paired daughter cell analyses that include single-cell 3D confocal imaging, single-cell transplants, single-cell RNA-seq, and single-cell transposase-accessible chromatin sequencing (ATAC-seq)-that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells.
造血干细胞（HSCs）通过自我更新和分化来维持体内平衡。随着年龄的增长，极性 HSCs 的频率会降低。HSCs 中的细胞极性由小 RhoGTPase 细胞分裂控制蛋白 42（Cdc42）的活性控制。在这里，我们通过一系列配对的子细胞分析（包括单细胞 3D 共聚焦成像、单细胞移植、单细胞 RNA-seq 和单细胞转座酶可及染色质测序（ATAC-seq））证明了，HSC 分裂的结果与有丝分裂前的极性状态密切相关，而极性状态又取决于干细胞中 Cdc42 的活性水平。衰老的无极性 HSCs 优先进行自我更新的对称分裂，导致子代干细胞的再生能力和淋巴样潜能降低，而年轻的极性 HSCs 则优先进行不对称分裂。数学建模结合实验数据表明，Cdc42 的不对称分配通过表观遗传机制在决定子细胞的潜能方面具有机械作用。因此，控制 HSC 极性的分子可能作为调节子细胞分裂模式的调节剂，从而调节子细胞的潜能。
