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Using barcodes to trace cell development

No. 42 | 16/08/2017 | by Rei

There are various concepts about how blood cells develop. However, they are based almost exclusively on experiments that solely reflect snapshots. In a publication in Nature, scientists from the German Cancer Research Center in Heidelberg now present a novel technique that captures the process in a dynamic way. Using a "random generator", the researchers label hematopoietic stem cells with genetic barcodes that enable them to trace which cell types arise from the stem cell. This method will facilitate whole new insights into the development of various tissues as well as cancer.

© Nicole Schuster/DKFZ

How do the multiple different cell types in the blood develop? Scientists have been pursuing this question for a long time. According to the classical model, different developmental lines branch out like in a tree. The tree trunk is composed of stem cells and the branches are made up of various types of progenitor cells that can give rise to a number of distinct cell types. Then it further branches off into the specialized blood cells, i.e., red blood cells, blood platelets and various types of white blood cells that are part of the immune system. In recent years, however, doubts about this model have arisen.

Hans-Reimer Rodewald, a scientist at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his co-workers wanted to capture the dynamic events in blood cell formation instead of merely taking snapshots. In close collaboration with a research team led by systems biologist Thomas Höfer, the scientists have developed a new technology that enables them to precisely follow the developmental tracks of cells. To this end, they label stem cells with a kind of genetic barcode in order to be able to clearly identify their offspring later.

"Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties," Rodewald said. "Our barcodes are different: They can be induced tissue-specifically and directly in the genome of mice – without influencing the animals' physiological development." The basis of the new technology is the so-called Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.

Weike Pei and Thorsten Feyerabend in Rodewald's team bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains nine small DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by ten genetic cutting sites called IoxP sites. By administering a pharmacological agent, the matching molecular scissors called "Cre" can be activated in the animals' hematopoietic stem cells. Then code elements are randomly rearranged or cut out. "This genetic random DNA barcode generator can generate up to 1.8 million genetic barcodes and we can identify the codes that arise only once in an experiment," Höfer said.

"The mice then do the rest of the work," said Rodewald. When these specially labeled hematopoietic stem cells divide and mature, the barcodes are preserved. In collaboration with the Max Delbrück Center for Molecular Medicine, the researchers have performed comprehensive barcode analyses in order to trace an individual blood cell back to the stem cell from which it originates.

These analyses have revealed that two large developmental branches start out from the hematopoietic stem cells of the mice: In one branch, T cells and B cells of the immune system develop; in the other, red blood cells as well as various other types of white blood cells such as granulocytes and monocytes form. All these cell types can arise from a single stem cell. "Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis," Rodewald emphasized.

The system developed by the Heidelberg researchers can also be used for other purposes besides studying blood cell development. This strategy can basically be applied in any tissue. In the future, it might also be used for experimentally tracing the origin of leukemias and other cancers.

Weike Pei, Thorsten B. Feyerabend, Jens Rössler, Xi Wang, Daniel Postrach, Katrin Busch, Immanuel Rode, Kay Klapproth, Nikolaus Dietlein, Claudia Quedenau, Wei Chen, Sascha Sauer, Stephan Wolf, Thomas Höfer and Hans-Reimer Rodewald: Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 2017, DOI: 10.1038/nature23653

A picture is available at:
http://www.dkfz.de/de/presse/pressemitteilungen/2017/bilder/Barcode_Blutstammzellen.jpg

Note on use of images related to press releases
Use is free of charge. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) permits one-time use in the context of reporting about the topic covered in the press release. Images have to be cited as follows: "Source: Nicole Schuster/DKFZ".
Distribution of images to third parties is not permitted unless prior consent has been obtained from DKFZ's Press Office (phone: ++49-(0)6221 42 2854, E-mail: presse@dkfz.de). Any commercial use is prohibited.

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Cancer Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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