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How to grow a human lung

Scientists have grown the first 3D mini lungs from stem cells.

Their study compliments 2D developments in the field such as lung tissue made from the scaffold of donated organs. The advantage of growing 3D structures is their organisation bears greater similarity to the human lung. The structures grown resemble both the large proximal airways and the small distal airways of a native, human lung.

According to lead author Dr Jason Spence: "We expected different cells types to form, but their organization into structures resembling human airways surprised us and is a very exciting result."

The work is published in ELIFE

Ingredients to Build a Lung

Embryonic stem cells

Proteins involved in lung development

Growth factors

Inhibitors of intestine development

Growing media

Petri dish

Protein mixture

Method for "morphogenesis in a dish": First, add protein ActivinA to stem cells and leave for four days. A type of tissue called endoderm will form. Endoderm is found in early embryos and gives rise to the lung, liver and several other internal organs.

Add Noggin, another protein, and a transforming growth factor. Leave for another four days. You will find the endoderm is induced to form 3D spherical structures called the foregut spheroids.

The next challenge is to make these structures expand and develop into lung tissue by exposing the cells to proteins involved in lung development.

Transfer spheroids to protein mixture and incubate at room temperature for 10 minutes until the mixture solidifies. Treat with additional proteins every four days and transfer into a new protein mixture every 10-15 days.

The resulting lung organoids should survive in culture for over 100 days and develop into well-organised structures containing cell types found in the lung. You will find the lung organoids are self-organizing, and do not require further manipulation to generate 3-dimensional tissues.

Previous studies have focused on forming the outer tissue of the lung (the epithelium). With this new method, you will be able to go one step further by also creating connective tissue (mesenchyme). In a more recent study, distal airway tissue was formed, which gives rise to the small airways less than 2mm in diameter. With the new method, cells of the large proximal airways also form, enabling more complete study of lung development and lung diseases.

Add the foregut spheroids to a lung scaffold from a human lung - use one deemed unsuitable for transplantation. On this scaffold, uou will find the organoids mature faster.

To study genetic disorders that affect lung development, produce stem cell lines from affected patients or introduce mutations to healthy cells. This will allow you to observe how a mutation affects cell differentiation, tissue organization, and tissue growth.

Since these structures were developed in a dish they lack blood vessels, a critical component for gas exchange, as well as other components of a native lung. The researchers hope to continue building onto their initial structure with increasingly complex components, eventually forming tiny organs able to perform gas exchange related to breathing.

Abstract
Recent breakthroughs in 3-dimensional (3D) organoid cultures for many organ systems have led to new physiologically complex in vitro models to study human development and disease. Here, we report the step-wise differentiation of human pluripotent stem cells (hPSCs) (embryonic and induced) into lung organoids. By manipulating developmental signaling pathways hPSCs generate ventral-anterior foregut spheroids, which are then expanded into human lung organoids (HLOs). HLOs consist of epithelial and mesenchymal compartments of the lung, organized with structural features similar to the native lung. HLOs possess upper airway-like epithelium with basal cells and immature ciliated cells surrounded by smooth muscle and myofibroblasts as well as an alveolar-like domain with appropriate cell types. Using RNA-sequencing, we show that HLOs are remarkably similar to human fetal lung based on global transcriptional profiles, suggesting that HLOs are an excellent model to study human lung development, maturation and disease.

The paper 'In vitro generation of human pluripotent stem cell derived lung organoids' can be freely accessed online at http://dx.doi.org/10.7554/eLife.05098. Contents, including text, figures, and data, are free to re-use under a CC BY 4.0 license.

About eLife Sciences Publications Ltd
eLife is a unique collaboration between the funders and practitioners of research to improve the way important research is selected, presented, and shared. eLife publishes outstanding works across the life sciences and biomedicine -- from basic biological research to applied, translational, and clinical studies. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. Learn more at elifesciences.org.

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