Journey from stem cell to blood cell uncovered
Researchers have catalogued previously undetected steps in the process by which stem cells become red and white blood cells. Errors in this process, which is called haematopoiesis, can lead to blood disorders and cancers.
The study, which is part of the BLUEPRINT project to understand blood disorders, newly identified thousands of cell-type specific transcripts, novel and unannotated splice junctions and alternative splicing events in blood cell development. These events change the amount or structure and behaviour of the proteins derived from a single gene. Alternative proteins can drive stem cells towards becoming different mature blood cells.
While haematopoiesis is relatively well understood at the level of DNA and gene activity, scientists dug deeper to discover how a cell's DNA is transcribed, cut and pasted, into RNA. These messenger molecules provide the instructions to build a protein. By understanding what is happening below the surface, scientists can begin to design diagnostics and therapies for blood disorders and, eventually, strategies for creating blood cells for regenerative medicines and transfusions.
"Cord blood stem cells are used to provide curative treatments for patients with blood cell cancers. After transplantation some donated stem cell preparation fail to regenerate certain cell types in the correct amounts. To tackle these problems, we need to understand blood cell development at the level of the transcripts and splice junctions that influence the fate of a hematopoietic stem cell."
Dr Lu Chen, first author from the Wellcome Trust Sanger Institute
"This catalogue provides the level of detail that we've been missing."
The hematopoietic stem cells and other committed progenitor cells needed for this study have not previously been studied in great detail because they are extremely rare in the bone marrow of adults. Researchers in this study were able to purify the cells from umbilical cord blood donations, where the concentration of these progenitor cells is surprisingly high.
Once they had the cells needed for analysis, scientists sequenced the RNA in exquisite detail, examining an average of 137 million aligned RNA sequences from each sample. This enormous quantity of data was then analysed using a complex statistical model that assessed the different transcript combinations and their concentrations at each stage of haematopoiesis to create a picture of the differentiation process and transcriptional diversity that has never been seen in such detail.
"These findings are essential if we are to discover the mutations underlying rare inherited haematological and immunological disorders. The data reported in this study is now publically available to researchers and can be used to develop better methods to elucidate the genetic basis of this category of rare diseases."
Professor Willem H Ouwehand, senior author at the University of Cambridge Department of Haematology and Honorary Faculty member at the Sanger Institute
The study is one of a suite of three papers that are the first to emerge from the BLUEPRINT project, a consortia of 41 research institutes that has received €30 million from the European Union to create a blueprint of haematopoietic epigenomes, the instruction manual that controls the creation and function of our blood cells.
"BLUEPRINT is a high-impact project that will contribute significantly to the International Human Epigenome Consortium. Our aim is to provide the data and resources needed to support research into blood-based diseases and speed the translation of advances into the clinic."
Dr Nicole Soranzo, senior author from the Sanger Institute