Human blood cells develop in a continuous process instead of a stepwise one

Every day, our body produces billions of new blood cells and even more in case of an infection or severe bleeding. They all arise from a small number of blood stem cells in the bone marrow ("hematopoietic" stem cells). For decades, it has been considered an established fact that blood stem cells differentiate in a stepwise process over many defined intermediate stages to ultimately mature into one of many types of blood cells such as red blood cells or T cells. Scientists imagined this process of hematopoiesis like a family tree.

Scientists from the departments of Lars Steinmetz, EMBL, Marieke Essers and Andreas Trumpp, German Cancer Research Center and HI-STEM, have now discovered that this model does not correspond to reality. Instead, the process of stem cell differentiation into mature blood cells is a continuous one in which the early progenitors of blood cells take one of many possible developmental paths without passing through distinct progenitor states.

In most prior investigations of the development of blood cells, researchers had analyzed populations of many thousand cells together. "In this way, one misses all transitory states in which individual cells in such a population might presently be," said Simon Rappel, who is one of the first authors of the current article.

In order to better comprehend this process, the Heidelberg team has now combined genome-wide gene expression analyses with functional tests – in thousands of single cells. "To evaluate the single-cell data we first had to develop new bioinformatics analysis software," said Lars Velten from EMBL. Based on the total of all analyses, the researchers could subsequently determine exactly when a specific stem cell "committed" to one of the possible lineages of development.

"Until now, scientists had assumed that the multipotent stem cells are succeeded in a stepwise process by various stages of oligopotent progenitors," Trumpp explained. "These progenitors go on developing into unipotent cell types at an advanced differentiation stage. However, what we found immediately following the stem cell state were progenitors that have already committed to one definite differentiation path, while bipotent or tripotent cells were really exceptions."

"This means that the commitment to one of the possible lineages happens much earlier than we thought," said Simon Haas, who is also one of the first authors. "We also did not find any groups of identical progenitor stages. Each cell was unique and – contrary to prior beliefs – followed a continuous development process, not a stepwise one."

"The results also have considerable impact on cancer research," said Marieke Essers from the DKFZ and HI-STEM. "Leukemias most likely arise from the blood stem cells themselves or their early progenitors. It is crucial to know the exact point in the development lineage where the leukemia-causing cells stray from normal differentiation. Scientists have believed, for example, that acute myeloid leukemia (AML), which mostly affects adults, originates from a particular progenitor cell type – which, as we have now shown, does not exist as such. Now, of course, the question is: Where does this leukemia in fact arise?"

"We have already started studying leukemia cells from patients using the same single-cell analysis," Trumpp said. "Our aim is to find out from which cells the leukemias really arise and which genetic networks reprogram normal progenitor cells into leukemia stem cells."

The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) is a partnership between the DKFZ and the Dietmar Hopp Foundation.

Lars Velten, Simon F. Haas, Simon Raffel, Sandra Blaszkiewicz, Saiful Islam, Bianca P. Hennig, Christoph Hirche, Christoph Lutz, Eike C. Buss, Daniel Nowak, Tobias Boch,Wolf-Karsten Hofmann ,Anthony D. Ho ,Wolfgang Huber , Andreas Trumpp, Marieke A. G. Essers and Lars M. Steinmetz: Human haematopoietic stem cell lineage commitment is a continuous process. Nature Cell Biology 2017, DOI 10.1038/ncb3493.