The complex journey from stem cell to blood cell

An international group of researchers has discovered previously undetected steps in haematopoiesis - the process by which stem cells become blood cells. The team established that a highly complex series of events determines the fate of closely related populations of blood progenitor cells.

The study, which is part of the international BLUEPRINT research project to understand blood disorders, identified thousands of differences in gene expression between blood cell types. These differences result from many specific events that are crucial for normal blood development; errors can lead to blood disorders including leukaemia.

Until this study, haematopoiesis was relatively well understood at the level of DNA. What was not known was how the genetic information in DNA was then transcribed to generate RNA, leading to protein formation. The research has discovered the extent to which the RNA is cut and pasted together in different ways during haematopoiesis, leading to specific forms of proteins for each of these stages. A comprehensive catalogue of transcription factors and other proteins that regulate the process has thus been generated.

“We have identified thousands of novel places where the RNA is processed in an alternative way,” said Professor Willem Ouwehand from the University of Cambridge and the Wellcome Trust Sanger Institute.

The journey haematopoietic stem cells take as they mature and differentiate into different types of blood cell.

The critical importance of the alternative splicing of RNA in blood cell development was illustrated by studying the role of two different forms of the same transcription factor in the formation of megakaryocytes, the progenitor cell for blood platelets. According to Professor Wendy Erber from The University of Western Australia, “Such events changed the amount, structure and behaviour of proteins derived from a single gene. Alternative proteins could drive stem cells towards becoming different mature blood cells.”

Writing in the journal Science, the researchers explained that they sequenced RNA from eight primary human haematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. Although the cells needed for the study are extremely rare in the bone marrow of adults, Professor Erber said the researchers were “able to purify the cells from umbilical cord blood donations, where the concentration of these progenitor cells is surprisingly high”.

“We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation,” the authors said. “In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes.”

As a result of the study, scientists can begin to design diagnostics and new therapies for blood disorders. The results will also be of great value in future studies in stem cell transplantation therapy, regenerative medicine and, according to Professor Ouwehand, “[discovering] the mutations underlying rare inherited haematological and immunological disorders”.

“The data reported in this study is now publicly available to researchers and can be used to develop better methods to elucidate the genetic basis of this category of rare diseases,” Professor Ouwehand concluded.