^{Stem Cell and Regenerative Medicine}

Biography

Biography: Simon Haas

Abstract

Multipotent hematopoietic stem cells are responsible for the livelong production of all blood and immune cells. In the classical model of hematopoiesis, blood formation is believed to occur through stepwise progression of hematopoietic stem cells following a tree-like hierarchy of oligo-, bi- and unipotent progenitors. However, this model is based on experimental approaches unable to describe how individual HSCs and their progeny enter lineage commitment during steady-state hematopoiesis. To establish a comprehensive model of human hematopoiesis, we have developed single-cell approaches that integrate single-cell RNA-sequencing with flow cytometric and functional lineage potency data. This allows us to reconstruct developmental trajectories and to gain a detailed view on lineage commitment of individual HSCs into all major branches of human haematopoiesis. We found that individual HSCs do not pass through discrete intermediate progenitor cell stages. In contrast, HSC lineage commitment occurs in a gradual manner best described by a continuous Waddington landscape with initially flat but progressively deepening valleys. Our data determine a detailed model of developmental trajectories within this landscape and demonstrates that distinct gene expression modules operate in a combinatorial manner to control stemness, early lineage priming and the subsequent progression into all major branches of hematopoiesis. These results establish the concept of a developmental continuum, which can replace the differentiation tree as a comprehensive model of human steady-state hematopoiesis and provide a basis for the understanding of hematopoietic malignancies.