Journey from stem cell to blood cell uncovered

BLUEPRINT study catalogues events that regulate blood cell creation

DOI: 10.1126/science.1251033
The journey hematopoietic stem cells take as they mature and differentiate into different types of blood cell. Abbreviations are explained in full in the paper.

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.

“This catalogue provides the level of detail that we’ve been missing.”

Dr Lu Chen First author from the Wellcome Trust Sanger Institute

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

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    BLUEPRINT is a large-scale research project receiving close to 30 million euro funding from the EU and involving 41 leading European universities, research institutes and industry entrepreneurs. The BLUEPRINT project aims to further the understanding of how our genes are activated or repressed in both healthy and diseased human cells. It aims to generate at least 100 reference epigenomes and study them to advance and exploit knowledge of the underlying biological processes and mechanisms in health and disease.

  • University of Cambridge

    The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 90 affiliates of the University have won the Nobel Prize. Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America. The University sits at the heart of one of the world’s largest technology clusters. The ‘Cambridge Phenomenon’ has created 1,500 hi-tech companies, 12 of them valued at over US$1 billion and two at over US$10 billion. Cambridge promotes the interface between academia and business, and has a global reputation for innovation.

  • NHS Blood and Transplant

    NHS Blood and Transplant collects blood and platelets from non-remunerated volunteer donors for use in the treatment of NHS patients. Every day about 7,000 units of blood and 1,100 platelet concentrates are provided to the NHS to support patient care. Professor Willem H Ouwehand is honorary consultant Haematologist for NHS Blood and Transplant.

  • The Wellcome Trust Sanger Institute

    The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

  • The Wellcome Trust

    The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.