Hematopoietic stem cells in the bone marrow
New research suggests the classical yet contested “tree” model of hematopoiesis is accurate.
In this model, the tree trunk is composed of hematopoietic stem cells (HSCs), and the branches consist of various progenitor cells that give rise to a number of distinct cell types.
Because previous research raised doubts about this model, investigators set out to track hematopoiesis more effectively than ever before.
The team used a “random generator” to label HSCs with genetic barcodes, and this allowed them to trace which cell types arise from an HSC.
Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his colleagues described this research in Nature.
“Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties,” Dr 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 Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.
The investigators bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains 9 DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by 10 genetic cutting sites called IoxP sites.
By administering a pharmacological agent, the matching molecular scissors, called “Cre,” can be activated in the animals’ HSCs. 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,” said study author Thomas Höfer, PhD, also of DKFZ.
When these specially labeled HSCs divide and mature, the barcodes are preserved.
The investigators performed comprehensive barcode analyses in order to trace an individual blood cell back to the HSC from which it originated.
These analyses revealed 2 large developmental branches “growing” from the HSC “tree trunk.” In one branch, T cells and B cells develop. In the other, red blood cells and other white blood cells, such as granulocytes and monocytes, form.
“Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis,” Dr Rodewald said.
He and his colleagues believe their genetic barcode system can be used for purposes other than studying blood cell development. In the future, it might be used for experimentally tracing the origin of leukemias and other cancers.
