Asymmetric organelle inheritance predicts human blood stem cell fate

Understanding human hematopoietic stem cell fate control is important for its improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear because of technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, nonrandom process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes, and recycling endosomes, show preferential asymmetric cosegregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell-cycle length, differentiation, and stem cell marker expression, whereas asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.

Automated summary

This study reveals the presence of asymmetric cell division in human blood stem cells, showing that lysosomes and active mitochondria are asymmetrically inherited and their inheritance is coordinated. There are also other organelles that show preferential asymmetric segregation with lysosomes. The asymmetric inheritance of lysosomes predicts the future fate of daughter cells, while the asymmetric inheritance of active mitochondria correlates with daughter metabolic activity.