Family tree of blood production reveals hundreds of thousands of stem cells
Humans have 10 times more blood-making stem cells than previously thought
Adult humans have many more blood-creating stem cells in their bone marrow than previously thought, ranging between 50,000 and 200,000 stem cells. Researchers from the Wellcome Sanger Institute and Wellcome – MRC Cambridge Stem Cell Institute developed a new approach for studying stem cells, based on methods used in ecology.
The results, published today (5 September) in Nature, present a new opportunity for studying, in humans, how stem cells throughout the body change during ageing and disease. Using whole genome sequencing to build and analyse a family tree of cells, this work could lead to insights into how cancers develop and why some stem cell therapies are more effective than others.
All of the organs in our body rely on stem cells in order to maintain their function. Adult stem cells found in tissues or organs are a self-sustaining population of cells whose offspring make all of the specialised cell types within a tissue.
Blood stem cells drive the production of blood, and are used in treatments and therapies such as bone marrow transplantations – a treatment for leukaemia that replaces cancerous blood cells with healthy blood stem cells.
However, blood stem cells in humans are not fully understood, with even some of the most basic questions, such as how many cells there are and how they change with age, not yet answered.
For the first time, scientists have been able to determine how many blood stem cells are actively contributing in a healthy human. Researchers adapted a method traditionally used in ecology for tracking population size to estimate that a healthy adult has between 50,000 and 200,000 stem cells contributing to their blood cells at any one time.
“We discovered that healthy adults have between 50,000 and 200,000 blood stem cells, which is about ten times more than previously thought. Whereas previous estimates of blood stem cell numbers were extrapolated from studies in mice, cats or monkeys, this is the first time stem cell numbers have been directly quantified in humans. This new approach opens up avenues into studying stem cells in other human organs and how they change between health and disease, and as we age.”
Scientists found the number of stem cells in the blood increases rapidly through childhood and reaches a plateau by adolescence. The number of stem cells stays relatively constant throughout adulthood.
In the study, researchers conducted whole genome sequencing on 140 blood stem cell colonies from a healthy 59-year-old man. The team adapted a capture-recapture* method, traditionally used in ecology to monitor species populations, to ‘tag’ stem cells and compare them to the population of blood cells.
“We isolated a number of stem cells from the blood and bone marrow and sequenced their genomes to find mutations. The mutations act like barcodes, each of which uniquely tags a stem cell and its descendants. We then looked for these mutations in the rest of the blood to see what fraction of blood cells carry the same barcodes and from this, we could estimate how many stem cells there were in total.”
Henry Lee-Six The first author from the Wellcome Sanger Institute
Current methods for measuring stem cell population size typically involve genome engineering, meaning they are limited to model organisms, such as mice. By analysing naturally-occurring mutations in human cells, researchers can use the accumulation of mutations to track stem cells to see how stem cell dynamics change over a person’s lifetime.
“This new approach is hugely flexible. Not only can we measure how many stem cells exist, we can also see how related they are to each other and what types of blood cells they produce. Applying this technique to samples from patients with blood cancers, we should now be able to learn how single cells outcompete normal cells to expand their numbers and drive a cancer. As the cost of genomic sequencing comes down, it is transforming scientific research such that studies previously thought to be impossibly large, are now becoming routine. It is a very exciting time to be working in this space.”
Dr David Kent A joint senior author from the Wellcome-MRC Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge
*Capture-recapture is a method commonly used in ecology to estimate a species’ population size. A portion of the population is captured, tagged, and released. Later, another portion is captured and the number of tagged individuals within the sample is counted. Since the number of marked individuals within the second sample should be proportional to the number of marked individuals in the whole population, an estimate of the total population size can be obtained by dividing the number of marked individuals by the proportion of marked individuals in the second sample. https://en.wikipedia.org/wiki/Mark_and_recapture
Henry Lee-Six et al. (2018) Population dynamics of normal human blood inferred from somatic mutations. Nature. DOI: 10.1038/s41586-018-0497-0
This work was supported by the Leukemia Lymphoma Society, Wellcome, Bloodwise, the William B Harrison Foundationand other funders. Please see the paper for the full list of funders.
The Cambridge Stem Cell Institute is a world-leading centre for stem cell research with a mission to transform human health through a deep understanding of stem cell biology. Our scientists study stem cell behaviour, both normal and pathological, and use their findings to improve the prevention, diagnosis and treatment of diseases. www.stemcells.cam.ac.uk/ Follow @SCICambridge
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, 98 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, 14 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. www.cam.ac.uk/
The Wellcome 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. To celebrate its 25th year in 2018, the Institute is sequencing 25 new genomes of species in the UK. Find out more at www.sanger.ac.uk or follow @sangerinstitute
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