Aging alters the epigenetic asymmetry of HSC division

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）在维持稳态的过程中平衡自我更新与分化。随着年龄的增长，极性HSCs的频率降低。HSCs中的细胞极性受小RhoGTPase细胞分裂调控蛋白42（Cdc42）活性的调控。本研究通过一系列包含单细胞3D共聚焦成像、单细胞移植、单细胞RNA测序和单细胞转座酶可及染色质测序（ATAC-seq）的成对子细胞分析，揭示了HSC分裂的结果与有丝分裂前细胞极性状态密切相关，而这一状态又反过来由干细胞中Cdc42活性的水平所决定。衰老的非极性HSCs倾向于进行自我更新的对称分裂，导致子代干细胞再生能力和淋巴潜能降低，而年轻的极性HSCs则倾向于进行非对称分裂。数学建模与实验数据的结合表明，Cdc42非对称分离在通过表观遗传机制决定子代细胞潜力方面起着机制性作用。因此，调控HSC极性的分子可能作为调节干细胞分裂方式、进而调控子代细胞潜力的调节剂。