̽��ֱ�� of Cambridge - Joo-Hyeon Lee

New method developed for ‘up-sizing’ mini organs used in medical research

sc604 — Mon, 08 Feb 2021 17:16:20 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, used their method to culture and grow a ‘mini-airway’, the first time that a tube-shaped organoid has been developed without the need for any external support.

Using a mould made of a specialised polymer, the researchers were able to guide the size and shape of the mini-airway, grown from adult mouse stem cells, and then remove it from the mould when it reached the point where it could support itself.

Whereas the organoids currently used in medical research are at the microscopic scale, the method developed by the Cambridge team could make it possible to grow life-sized versions of organs. Their results are reported in the journal Advanced Science.

Organoids are tiny, three-dimensional cell assemblies that mimic the cell arrangement of fully-grown organs. They can be a useful way to study human biology and how it can go wrong in various diseases, and possibly how to develop personalised or regenerative treatments. However, assembling them into larger organ structures remains a challenge.

Other research teams have experimented with 3D printing techniques to develop larger mini-organs, but these often require an external support structure.

“Mini-organs are very small and highly fragile,” said Dr Yan Yan Shery Huang from Cambridge’s Department of Engineering, who co-led the research. “In order to scale them up, which would increase their usefulness in medical research, we need to find the right conditions to help the cells self-organise.”

Huang and her colleagues have proposed a new organoid engineering approach called Multi-Organoid Patterning and Fusion (MOrPF) to grow a miniature version of a mouse airway using stem cells. Using this technique, the scientists achieved faster assembly of organoids into airway tubes with uninterrupted passageways. ̽��ֱ��mini-airways grown using the MOrPF technique showed potential for scaling up to match living organ structures in size and shape, and retained their shape even in the absence of an external support.

̽��ֱ��MOrPF technique involves several steps. First, a polymer mould – like a miniature version of a cake or jelly mould – is used to shape a cluster of many small organoids. ̽��ֱ��cluster is released from the mould after one day, and then grown for a further two weeks. ̽��ֱ��cluster becomes one single tubular structure, covered by an outer layer of airway cells. ̽��ֱ��moulding process is just long enough for the outer layer of the cells to form an envelope around the entire cluster. During the two weeks of further growth, the inner walls gradually disappear, leading to a hollow tubular structure.

“Gradual maturation of the cells is really important,” said Dr Joo-Hyeon Lee from Cambridge’s Wellcome – MRC Cambridge Stem Cell Institute, who co-led the research. “ ̽��ֱ��cells need to be well-organised before we can release them so that the structures don’t collapse.”

̽��ֱ��organoid cluster can be thought of like soap bubbles, initially packed together to form to the shape of the mould. In order to fuse into a single gigantic bubble from the cluster of compressed bubbles, the inner walls need to be broken down. In the MOrPF process, the fused organoid clusters are released from the mould to grow in floating, scaffold-free conditions, so that the cells forming the inner walls of the fused cluster can be taken out of the cluster. ̽��ֱ��mould can be made into different sizes or shapes, so that the researchers can pre-determine the shape of the finished mini-organ.

“ ̽��ֱ��interesting thing is, if you think about the soap bubbles, the resulting big bubble is always spherical, but the special mechanical properties of the cell membrane of organoids make the resulting fused shape preserve the shape of the mould,” said co-author Professor Eugene Terentjev from Cambridge’s Cavendish Laboratory.

̽��ֱ��team say their method closely approximated the natural process of organ tube formation in some animal species. They are hopeful that their technique will help create biomimetic organs to facilitate medical research.

̽��ֱ��researchers first plan to use their method to build a three-dimensional ‘organ on a chip’, which enables real-time continuous monitoring of cells, and could be used to develop new treatments for disease while reducing the number of animals used in research. Eventually, the technique could also be used with stem cells taken from a patient, in order to develop personalised treatments in future.

̽��ֱ��research was supported in part by the European Research Council, the Wellcome Trust and the Royal Society.

Reference:
Ye Liu et al. ‘Bio-assembling Macro-Scale, Lumenized Airway Tubes of Defined Shape via Multi-Organoid Patterning and Fusion.’ Advanced Science (2021). DOI: 10.1002/advs.202003332

A team of engineers and scientists has developed a method of ‘up-sizing’ organoids: miniature collections of cells which mimic the behaviour of various organs and are promising tools for the study of human biology and disease.

We need to find the right conditions to help the cells in mini-organs self-organise

Yan Yan Shery Huang

Catherine Dabrowska

3D projection of a multi-organoid aggregate

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Yes

‘Mini-lungs’ reveal early stages of SARS-CoV-2 infection

cjb250 — Fri, 23 Oct 2020 08:29:27 +0000

To date, there have been more than 40 million cases of COVID-19 and almost 1.13 million deaths worldwide. ̽��ֱ��main target tissues of SARS-CoV-2, the virus that causes COVID-19, especially in patients that develop pneumonia, appear to be alveoli – tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide to exhale.

To better understand how SARS-CoV-2 infects the lungs and causes disease, a team of scientists from the UK and South Korea turned to organoids – ‘mini-organs’ grown in three dimensions to mimic the behaviour of tissue and organs.

̽��ֱ��team used tissue donated to tissue banks at the Royal Papworth Hospital NHS Foundation Trust and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� NHS Foundations Trust, UK, and Seoul National ̽��ֱ�� Hospital to extract a type of lung cell known as human lung alveolar type 2 cells. By reprogramming these cells back to their earlier ‘stem cell’ stage, they were able to grow self-organising alveolar-like 3D structures that mimic the behaviour of key lung tissue.

Dr Joo-Hyeon Lee, co-senior author, and a Group Leader at the Wellcome-MRC Cambridge Stem Cell Institute, ̽��ֱ�� of Cambridge, said: “We still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease. Our approach has allowed us to grow 3D models of key lung tissue – in a sense, ‘mini-lungs’ – in the lab and study what happens when they become infected.”

̽��ֱ��team infected the organoids with a strain of SARS-CoV-2 taken from a patient in South Korea who was diagnosed with COVID-19 on 26 January 26 2020 after traveling to Wuhan, China. Using a combination of fluorescence imaging and single cell genetic analysis, they were able to study how the cells responded to the virus.

When the 3D models were exposed to SARS-CoV-2, the virus began to replicate rapidly, reaching full cellular infection just six hours after infection. Replication enables the virus to spread throughout the body, infecting other cells and tissue.

Around the same time, the cells began to produce interferons – proteins that act as warning signals to neighbouring cells, telling them to activate their antiviral defences. After 48 hours, the interferons triggered the innate immune response – its first line of defence – and the cells started fighting back against infection.

Sixty hours after infection, a subset of alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.

Although the researchers observed changes to the lung cells within three days of infection, clinical symptoms of COVID-19 rarely occur so quickly and can sometimes take more than ten days after exposure to appear. ̽��ֱ��team say there are several possible reasons for this. It may take several days from the virus first infiltrating the upper respiratory tract to it reaching the alveoli. It may also require a substantial proportion of alveolar cells to be infected or for further interactions with immune cells resulting in inflammation before a patient displays symptoms.

“Based on our model we can tackle many unanswered key questions, such as understanding genetic susceptibility to SARS-CoV-2, assessing relative infectivity of viral mutants, and revealing the damage processes of the virus in human alveolar cells,” said Dr Young Seok Ju, co-senior author, and an Associate Professor at Korea Advanced Institute of Science and Technology. “Most importantly, it provides the opportunity to develop and screen potential therapeutic agents against SARS-CoV-2 infection.”

“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue,” added Dr Lee.

̽��ֱ��research was a collaboration involving scientists from the ̽��ֱ�� of Cambridge, UK, and the Korea Advanced Institute Science and Technology (KAIST), Korea National Institute of Health, Institute for Basic Science (IBS), Seoul National ̽��ֱ�� Hospital and GENOME INSIGHT Inc. in South Korea.

Reference
Jeonghwan Youk et al. Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2. Cell Stem Cell; 21 Oct 2020; DOI: 10.1016/j.stem.2020.10.004

Funding
̽��ֱ��research was supported by: the National Research Foundation of Korea; Research of Korea Centers for Disease Control and Prevention; Ministry of Science and ICT of Korea; Ministry of Health & Welfare, Republic of Korea; Seoul National ̽��ֱ�� College of Medicine Research Foundation; European Research Council; Wellcome; the Royal Society; Biotechnology and Biological Sciences Research; Suh Kyungbae Foundation; and the Human Frontier Science Program.

Image caption
Representative image of three-dimensional human lung alveolar organoid showing alveolar stem cell marker, HTII-280 (red) and SARS-CoV-2 entry protein, ACE2 (green). (Credit: Jeonghwan Youk, Taewoo Kim, and Seon Pyo Hong)

‘Mini-lungs’ grown from tissue donated to Cambridge hospitals have provided a team of scientists from South Korea and the UK with important insights into how COVID-19 damages the lungs. Writing in the journal Cell Stem Cell, the researchers detail the mechanisms underlying SARS-CoV-2 infection and the early innate immune response in the lungs.

We still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease. Our approach has allowed us to grow 3D models of key lung tissue – in a sense, ‘mini-lungs’ – in the lab and study what happens when they become infected

Joo-Hyeon Lee

Jeonghwan Youk, Taewoo Kim, and Seon Pyo Hong

Representative image of three-dimensional human lung alveolar organoid

Yes

Strategic partner: AstraZeneca

skbf2 — Mon, 11 Nov 2019 16:20:03 +0000

Scientists at AstraZeneca, a global biopharmaceutical company, have been working with Cambridge ̽��ֱ�� for more than two decades. What are the secrets of their success?