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World’s first cell atlas of developing liver created by Cambridge scientists

The world’s first cell atlas of the human developmental liver has been created, giving fresh insight into how the blood and immune systems develop in the foetus.

A high-resolution resource, it will aid our understanding of normal development and efforts to tackle diseases that can form during development, such as leukaemia and immune disorders.

Dr Sarah Teichmann FMedSci, Cellular Genetics Programme Head, WTSI,in front of the computer cluster at Sanger. Picture: Pari Naderi. (19490449)
Dr Sarah Teichmann FMedSci, Cellular Genetics Programme Head, WTSI,in front of the computer cluster at Sanger. Picture: Pari Naderi. (19490449)

The cell atlas maps how the cellular landscape within the developing liver changes between the first and second trimesters of pregnancy, including how stem cell from the liver seed other tissues, supporting the high demand for oxygen required for growth.

Researchers from the Wellcome Sanger Institute in Hinxton, the Wellcome – MRC Cambridge Stem Cell Institute, University of Cambridge, Newcastle University and their collaborators created the atlas by using single cell technology to analyse 140,000 liver cells and 74,000 skin, kidney and yolk sac cells.

In adults, it is bone marrow that is primarily responsible for the creation of blood and immune cells in a process called haematopoiesis.

In early embryonic life, the yolk sac and liver play a key role in creating these cells, which then seed peripheral tissues such as skin, kidney and ultimately bone marrow.

But until now, the precise process of how blood and immune systems develop in humans has been unknown.

Isolating cells from the developing liver, the researchers were able to identify them by what genes they were expressing and discover what the cells looked like.

They tagged haematopoietic cells in sections of developmental liver using heavy metal markers in order to map them to their location.

Prof Muzlifah Haniffa, a senior author of the study from Newcastle University and senior clinical fellow at the Wellcome Sanger Institute, said: “Until now research in this area has been a little bit like blindfolded people studying an elephant, with each describing just a small part of it.

“This is the first time that anyone has described the whole picture, how the blood and immune systems develop in such detail. It’s been an extraordinary, multidisciplinary effort that is now available as a tool for the whole scientific community.”

The scientists learned that during foetal development, ‘mother’ haematopoietic stem cells stay in the liver. But the liver alone cannot supply enough red blood cells, so the next generation ‘daughter’ cells – called progenitor cells – travel to other tissues, maturing in places such as the skin. Thee, they develop into red blood cells to help meet the high demand for oxygen in the developing foetus.

Dr Elisa Laurenti, a senior author from the Wellcome – MRC Cambridge Stem Cell Institute and the Department of Haematology at the University of Cambridge, said: “We knew that as adults age our immune system changes. This study shows how the liver’s ability to make blood and immune cells changes in a very short space of time, even between seven and 17 weeks post-conception.

“If we can understand what makes the stem cells in the liver so good at making red blood cells, it will have important implications for regenerative medicine.”

The study, published in Nature, also involved the mapping of genes involved in immune deficiencies to reveal which cells were expressing them.

Haematopoiesis. Picture: Newcastle University (19619822)
Haematopoiesis. Picture: Newcastle University (19619822)

It is known that gene mutations can lead to immune disorders such as leukaemia.

A better understanding of the development of healthy liver functions could aid our understanding of how to treat such conditions.

The work is part of the ambitious effort to create the first complete Human Cell Atlas.

Dr Katrina Gold, genetics and molecular sciences portfolio manager at Wellcome, said: “Our immune system is vital in helping to protect us from disease, yet we know very little about how immune cells develop and behave in the early embryo. This study is hugely important, laying a critical foundation for future research that could help improve our understanding of disorders linked to the early immune system, such as childhood leukaemias.

“The Human Cell Atlas has the potential to transform our understanding of health and disease and we’re excited to see these first discoveries from our Wellcome-funded multidisciplinary team of scientists.”

Dr Sarah Teichmann, a senior author from the Wellcome Sanger Institute, University of Cambridge and co-chair of the Human Cell Atlas organising committee, said: “The first comprehensive cellular map of the developmental liver is another milestone for the Human

Cell Atlas initiative.

“The data is now freely available for anyone to use and will be a great resource to better understand healthy cellular development and disease-causing genetic mutations.”

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