Cytokines Instruct Hematopoietic Lineage Choice

Abstract SCI-13

The molecular control of multipotent cell lineage choice is one of the central questions in stem cell biology. Since decades, it is controversial whether cell extrinsic factors can actively influence lineage decisions of hematopoietic cells (instructive model). Alternatively, they may only allow the survival and proliferation of already unilineage-restricted cells, which have chosen one lineage by cell-autonomous mechanisms (selective / permissive model). One major reason for this longstanding controversy is the fact that hematopoiesis is usually followed by analyzing populations of cells - rather than individual cells - at very few time points of an experiment and without knowing their individual identities. However, the alternative lineage choice models can only be distinguished by constantly observing individual cell fates throughout differentiation.We therefore applied novel computer aided culture, imaging and cell tracking approaches to follow the fate of individual cells over many days. Analysis of primary mouse multipotent hematopoietic cell differentiation finally provided proof for the lineage instructive action of hematopoietic cytokines. This finding is of fundamental importance for our understanding of the molecular control of lineage choice. It shows that cell extrinsic signaling influences the - currently unknown - cell intrinsic molecular lineage choice and commitment machinery. Our novel approaches now allow identification of the signaling pathways mediating lineage instruction and their targets with the required precision. Moreover, we are developing technology for the quantification of lineage specific transcription factor proteins in individual living cells. This novel kind of continuous, live and quantitative molecular and cellular data is used for modeling the control of cell fates through integration of cell extrinsic signals with cell intrinsic molecular states.