Stem cells located in the bone marrow generate and control the production of blood and immune cells. Researchers from EMBL, DKFZ and HI-STEM have now developed new methods to reveal the three-dimensional organization of the bone marrow at the single cell level. Using this approach the teams have identified previously unknown cell types that create specific local environments required for blood generation from stem cells. The study, published in Nature Cell Biology, reveals an unexpected complexity of the bone marrow and its microdomains at an unprecedented resolution and provides a novel scientific basis to study blood diseases such as leukemias.
In the published study researchers from European Molecular Biology Laboratory (EMBL), the German Cancer Research Center (DKFZ) and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine* (HI-STEM gGmbH) present new methods permitting the characterisation of complex organs. The team focused their research on the murine bone marrow, as it harbours blood stem cells that are responsible for life-long blood production. Because of the ability to influence stem cells and to sustain blood production, there is a growing interest in exploiting the bone marrow environment, also called niche, as a target for novel leukaemia treatments. "So far, very little was known about how different cells are organised within the bone marrow and how they interact to maintain blood stem cells," explains Chiara Baccin, post-doc in the Steinmetz Group at EMBL. "Our approach unveils the cellular composition, the three-dimensional organisation and the intercellular communication in the bone marrow, a tissue that has thus far been difficult to study using conventional methods," further explains Jude Al-Sabah, PhD student in the Haas Group at HI-STEM and DKFZ.
In order to understand which cells can be found in the bone marrow, where they are localised and how they might impact on stem cells, the researchers combined single-cell and spatial transcriptomics with novel computational methods. By analysing the RNA content of individual bone marrow cells, the team identified 32 different cell types, including extremely rare and previously unknown cell types. "We believe that these rare 'niche cells' establish unique environments in the bone marrow that are required for stem cell function and production of new blood and immune cells," explains Simon Haas, group leader at the DKFZ and HI-STEM, and one of the initiators of the study.
Using novel computational methods, the researchers were not only able to determine the organisation of the different cell types in the bone marrow in 3D, but could also predict their cellular interactions and communication. "It's the first evidence that spatial interactions in a tissue can be deduced computationally on the basis of genomic data," explains Lars Velten, staff scientist in the Steinmetz Group.
"Our dataset is publicly accessible to any laboratory in the world and it could be instrumental in refining in vivo studies," says Lars Steinmetz, group leader and director of the Life Science Alliance at EMBL Heidelberg. The data, which is now already used by different teams all over the world, is accessible via a user-friendly web app.
The developed methods can in principle be used to analyse the 3D organisation of any organ at the single cell level. "Our approach is widely applicable and could also be used to study the complex pathology of human diseases such as anemia or leukemia" highlights Andreas Trumpp, managing director of HI-STEM and division head at DKFZ.
*The Heidelberg Institute for Stem Cell Research and Experimental Medicine (HI-STEM) gGmbH was founded in 2008 as a public-private partnership between the DKFZ and the Dietmar Hopp Foundation
Chiara Baccin, Jude Al-Sabah, Lars Velten, Patrick M. Helbling, Florian Grünschläger, Pablo Hernández-Malmierca, César Nombela-Arrieta, Lars M. Steinmetz, Andreas Trumpp, and Simon Haas: Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization.
Nature Cell Biology 2019, https:/
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Picture Caption: Three dimensional segmentation of a bone marrow region. Different niche cells (green and red dots) and blood vessels (grey) are highlighted.
Source: DKFZ, EMBL and University Hospital Zurich
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. At DKFZ, more than 1,300 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.
DKFZ's Cancer Information Service (KID) provides individual answers to all questions about cancer for patients, the general public, and health care professionals. Jointly with partners from Heidelberg University Hospital, DKFZ runs the National Center for Tumor Diseases (NCT) located in Heidelberg and Dresden, and, also in Heidelberg, the Hopp Children's Cancer Center (KiTZ). In the German Cancer Consortium (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 at the NCT and DKTK sites is an important contribution to the endeavor of translating promising approaches from cancer research into the clinic in order to improve 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.