Abstract

Recent advances in the non-invasive genetic labeling and barcoding of hematopoietic stem cells (HSCs) now allow tracing their fates under physiological conditions in vivo. We have shown that time-resolved data obtained by lineage tracing of stem cells contain information on the differentiation rates of stem and progenitor cells and provided computational inference tools for these rates. Our data, and data by others, show remarkably low output of HSCs in unchallenged adult mice while multipotent progenitor cells have both high output and considerable self-renewal in vivo. I will review these findings and show how we have recently used the combination of lineage tracing and computational rate inference to dissect the response of the hematopoietic system to various challenges. In response to strong natural challenges, such as sepsis, we uncover transiently increased progenitor cell output whereas the contribution of HSCs to hematopoietic cell production remains low throughout. Our findings argue in favor of regulatory feedback acting on progenitor cells and do not support the view of quiescent HSCs as a reserve for responding to challenges; I will propose an alternative function of tip stem cells in hematopoiesis. By way of an outlook, I will outline how rate inference is also advancing our understanding of molecular regulation of gene expression.