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14.08.17 New model of human lung development provided by Rawlins lab organoid system

last modified Sep 06, 2017 09:02 PM
In this eLife paper Emma Rawlins' lab, with colleagues in Cambridge and London, describe their new human lung distal tip epithelium cultures
14.08.17 New model of human lung development provided by Rawlins lab organoid system

Section through P6 tip organoid showing single layer epithelium

Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids

Nikolić MZ et al. (2017) Elife Jun 30;6 pii:e26575. DOI: 10.7554/eLife.26575

 

eLife digest

Degenerative lung disease occurs when the structure of the lungs breaks down, which makes it harder to get enough oxygen into the bloodstream. Most, but not all, cases occur in smokers and ex-smokers or people who have been exposed to a lot of air pollution. Currently, there is no way to reverse the damage, and even slowing the progress of the disease is extremely difficult. Some researchers are looking for ways to treat patients with degenerative lung diseases by regenerating the surface of their lungs. However, it is still not clear what the most effective route towards this long-term goal will be.

One approach to lung regeneration is to use findings from developmental biology to understand how embryos normally build the gas exchange surfaces in the lungs. This knowledge may allow scientists to trigger a similar process in an adult lung to renew or replace any diseased tissue. Alternatively, cells could be collected from patients, reprogrammed and then coaxed into becoming a gas exchange surface in the laboratory. Such a “lung-in-a-dish” could be used to understand how degenerative diseases develop, to discover and test new drugs, or even to treat the patient directly via a transplant.

To date, the embryonic development of lungs has mostly been studied using mouse lungs as a model system. However, it was not clear if human lungs actually develop in similar ways to mouse lungs, and whether using mice is a valid research strategy.

Nikolić et al. compared embryonic lungs from humans and mice and showed that they are indeed very similar in terms of the cell types that they contain and how they mature. However, some key differences were identified that can only be explored in human cells and tissue. Nikolić et al. went on to identify conditions that allowed them to grow cells from human embryonic lungs indefinitely in a dish. These cells can now be used to investigate the aspects of lung development that are specific to humans.

Together these findings provide a useful guide to allow scientists to coax human cells growing in a laboratory to become lung cells. Further improvements to this process will make the lungs-in-a-dish more true to the real organs, meaning that they could be used to better understand lung disease and identify new medicines. In the longer term, Nikolić et al. hope to gain enough insight from the human lung-in-a-dish model to eventually be able to regenerate the lungs of patients with degenerative lung disease. However, this possibility is still many years away.

Abstract from the paper

The embryonic mouse lung is a widely used substitute for human lung development. For example, attempts to differentiate human pluripotent stem cells to lung epithelium rely on passing through progenitor states that have only been described in mouse. The tip epithelium of the branching mouse lung is a multipotent progenitor pool that self-renews and produces differentiating descendants.

We hypothesized that the human distal tip epithelium is an analogous progenitor population and tested this by examining morphology, gene expression and in vitro self-renewal and differentiation capacity of human tips. These experiments confirm that human and mouse tips are analogous and identify signalling pathways that are sufficient for long-term self-renewal of human tips as differentiation-competent organoids.

Moreover, we identify mouse-human differences, including markers that define progenitor states and signalling requirements for long-term self-renewal. Our organoid system provides a genetically-tractable tool that will allow these human-specific features of lung development to be investigated.

 

Further resources

Related blog post, 'The evolution from mouse to human models of lung development', by first author Marko Nicolić on The Node.

Insight article in eLife, 'Organ Development: Tips from the embryonic lung'.

 

Read more about research in the Rawlins lab.

Watch Emma Rawlins describe her work on lung development on YouTube.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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