Pioneering scientists at Great Ormond Street Hospital (GOSH), the UCL Great Ormond Street Institute of Child Health (ICH) and the Francis Crick Institute have grown human intestinal grafts using stem cells from patient tissue that could one day lead to personalised transplants for children with intestinal failure, according to a study published in Nature Medicine.
Children with intestinal failure cannot absorb the nutrients that are essential for their overall health and development. This may be due to a disease or injury to their small intestine.
This was the case for eight-year-old Enzo, pictured above, who developed necrotizing enterocolitis (NEC) shortly after he was born and had surgery at GOSH to remove his large intestine, colon, and most of his small intestine.
In these cases, children like Enzo can be fed intravenously via a process called parenteral nutrition, however this can be associated with severe complications such as line infections and liver failure. If complications arise or in severe cases, these children may need a transplant. However, there is a shortage of suitable donor organs and problems can arise after surgery, such as the body rejecting the transplant.
Enzo’s Dad, Pier Francesco, says, “If Enzo was offered a bowel transplant today, I couldn’t accept it because there’s a risk of it rejecting. He hasn’t got enough bowel left to do anything with if it did reject. If there was an option for children to receive rejection-free transplants, that would be the holy grail. It would be incredible if children didn’t have to go through everything Enzo has. This latest research sounds very promising – research offers hope and as parents, that’s all we’ve got.” You can read more about Enzo’s experience here.
In their proof-of-concept study, the research team showed how intestinal stem cells and small intestinal or colonic tissue taken from patients can be used to grow the important inner layer of small intestine in the laboratory with the capacity to digest and absorb peptides and digest sucrose in food.
This is the first step in efforts to engineer all the layers of the intestine for transplantation. The researchers hope that one day, laboratory grown organs could offer a safe and longer-lasting alternative to traditional donor transplants for children like Enzo, pictured above.
“Although this research is in the lab right now, we’re concentrating on making this a realistic and safe treatment option,”
explains senior author NIHR Professor Paolo De Coppi (pictured above), Consultant Paediatric Surgeon at GOSH and Head of Surgery, Stem Cells & Regenerative Medicine Section at the ICH.
“What’s significant here is we’ve shown that scaffolds can be created using tissue from the colon, not only tissue from the small intestine. In practice, it is often easier to obtain tissue from the colon, so this could make the approach much more feasible. Moreover, the colon is often preserved in children who have lost their small bowel, and it could be possible to transplant part of the small bowel lining in the colon, rather than engineering or transplanting an entire bowel. It’s an important step forward in regenerative medicine and we’re optimistic about what this means for patients, but more research lies ahead before we can safely and effectively translate this approach to treatment.”
Dr Vivian Li, senior author and group leader of the Stem Cell and Cancer Biology Laboratory at the Crick, adds: “It’s urgent that we find new ways to care for children without a working intestine because, as they grow older, complications from parental nutrition can arise.”
“We’ve set out a process to grow one layer of intestine in the laboratory, moving us a step closer to being able to offer these patients a form of regenerative medicine, which uses materials created from their own tissue. This would reduce some of the risks that transplant patients face, such as their immune system attacking the transplant.”
How do you grow a mini-gut?
The researchers took small biopsies of intestine from 12 children who either had intestinal failure or were at risk of developing the condition. In the lab, they then stimulated the biopsy cells to grow into ‘mini-guts’, also known as intestinal organoids, generating over 10 million intestinal stem cells from each patient over the course of four weeks.
The researchers also collected small intestine and colon tissue, that would otherwise have been discarded, from other children undergoing essential surgery to remove parts of their gut. Using laboratory techniques, cells were removed from these tissues leaving behind a skeleton structure which formed scaffolds.
The researchers placed the ‘mini-guts’ onto these scaffolds, where they grew on this structure to form a living graft. Due to specific culture conditions, the stem cells changed into many of the different types of cells that exist in the small intestine. The grafts were able to digest and absorb peptides, the building blocks of proteins, as well as digest sucrose into glucose sugars.
As well as proving that biopsies taken from children could be used to grow functioning intestinal grafts, the researchers also demonstrated that the grafts survive and mature when transplanted into mice.
Building on success
“Now that we’ve shown the grafts are successful on a small scale, the next crucial steps will be to start growing the other layers of the intestine such as muscle and blood vessels, whilst also scaling up our methods to create viable grafts relevant to individual patient needs,”
says Laween Meran, lead author, Gastroenterology Registrar and Clinical Research Training Fellow at the Stem Cell and Cancer Biology Laboratory at the Crick and the ICH.
This work was funded by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, the Wellcome Trust, and the Horizon2020 INTENS Consortium; Paolo de Coppi is supported by National Institute of Health Research (NIHR) Professorship and Oak Foundation, via Great Ormond Street Hospital Children’s Charity (GOSH Charity); and Laween Meran is funded by a Clinical Research Training Fellowship from the NIHR, UCL, the NIHR Great Ormond Street Hospital Biomedical Research Centre and the Crick.
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The Nature Medicine paper entitled ‘Engineering transplantable jejunal mucosal grafts using primary patient-derived organoids for children with intestinal failure’ is available at https://www.nature.com/articles/s41591-020-1024-z
About Great Ormond Street Hospital for Children NHS Foundation Trust
Founded in 1852, Great Ormond Street Hospital (GOSH) is one of the world’s leading children’s hospitals with the broadest range of dedicated, children’s healthcare specialists under one roof in the UK. With more than 252,000 outpatient and 43,000 inpatient visits every year, the hospital’s pioneering research and treatment gives hope to children from across the UK with the rarest, most complex and often life-threatening conditions. As an international centre of excellence in child healthcare, our patients and families are central to everything we do – from the moment they come through the door and for as long as they need us. Visit www.gosh.nhs.uk
Research at GOSH is underpinned by support from the National Institute of Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) and GOSH Charity.
About the UCL Great Ormond Street Institute of Child Health (ICH)
The UCL Great Ormond Street Institute of Child Health (ICH) is part of the Faculty of Population Health Sciences within the School of Life and Medical Sciences at University College London.
Together with its clinical partner Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH), it forms the UK's only paediatric National Institute for Health Research (NIHR) Biomedical Research Centre and has the largest concentration of children's health research in Europe.
For more information visit www.ucl.ac.uk/child-health
The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases.
An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London.
The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe.