Scientists from the German Cancer Research Center (DKFZ), the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) and the European Molecular Biology Laboratory (EMBL) used a new combination of analysis methods to study in single cells how blood stem cells in the bone marrow differentiate into mature blood cells. Their results have turned textbook knowledge of the past decades upside down.
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.
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.