2021 - Asymmetric Cell Division Controls Hematopoietic Stem Cell Metabolic Activation and Differentiation

Abstract

Hematopoietic stem cells (HSCs) maintain their numbers while also differentiating to replenish the entire blood system lifelong. Asymmetric cell division has been hypothesized as the underlying mechanism balancing HSC self-renewal and differentiation. In this model, future asymmetric daughter cell fates are prospectively determined by a mechanism linked to mitosis, e.g. the unequal inheritance of cell fate determinants to the two daughters. However, due to lacking technology, this mechanism could never been shown directly. It is therefore also possible that HSCs do not divide asymmetrically, and commitment to differentiation is determined by post-mitotic mechanisms. Asymmetric inheritance of cell fate determinants has been reported in in- and vertebrate progenitor divisions of other tissues. However, the low frequency of HSCs and the technical challenges associated with reliable continuous quantitative analysis of single suspension cells have prevented the study of events during HSC mitosis. Few studies therefore provide evidence for asymmetric inheritance of proteins during hematopoietic stem and progenitor cell (HSPC) division, and none was able to demonstrate that future daughter cell fates correlate with this asymmetric inheritance. Here, using novel continuous quantitative live single cell imaging, we identify several molecules which are asymmetrically inherited along with the lysosomal machinery during HSC divisions. Importantly, we demonstrate that this asymmetric inheritance also predicts future metabolic activation and differentiation of the HSC daughters. We provide the first direct quantitative evidence that HSCs utilize asymmetric cell division, that future daughter cells fates are prospectively determined by asymmetric mitotic molecule inheritance, and provides insights into the underlying molecular mechanisms for improved therapeutic HSC manipulation.