2019 – ASYMMETRIC CELL DIVISION MODULATES HUMAN HEMATOPOIETIC STEM CELL FATES

Abstract

Effective manipulation of clinically relevant umbilical cord blood-derived human hematopoietic stem cell (hHSC) fate decisions remains an important goal for improved therapies. Based on observations in other model organisms, it was postulated that asymmetric cell division (ACD) regulates hHSC fate decisions of self-renewal and differentiation. In ACD, daughter cell fates are determined during cell division, e.g., by the asymmetric inheritance of cell fate determinants. Previous studies suggested the asymmetric inheritance of factors during progenitor divisions. However, due to the lack of tools for sufficient prospective hHSC enrichment, quantification of asymmetric inheritance and future daughter cell behaviors in the same experiment, hHSC ACD remained hypothetical. Here, we use continuous quantitative long-term single-cell imaging of highly purified hHSCs to identify factors and organelles that are asymmetrically inherited during hHSC divisions. Importantly, this asymmetric inheritance correlates with future asymmetric adhesion, motility, cell cycle progression, marker production, and metabolic activity in hHSC daughters. We further show, using novel real-time computational differentiation landscapes and in-silico hHSC purification, that this asymmetric inheritance also correlates with future expression of stem cell markers, and that culture conditions known to expand hHSCs increase symmetric cell divisions. We thus provide the first direct quantitative evidence that ACD exists in human hematopoietic stem and progenitor cells and modulates future daughter cells fates by the inheritance of factors during division. We provide insights into the underlying molecular mechanisms, and the exciting possibility to manipulate ACD and hHSC fate decision for improved therapy.