Scientists from the University of Michigan have grown the first 3D mini lungs from stem cells. The study, published in eLife, compliments other developments in the field such as growing mainly 2D structures and building lung tissue from the scaffold of donated organs.
The advantage of growing 3D structures is that their organisation bears greater similarity to the human lung. The scientists succeeded in growing structures resembling both the large proximal airways and the small distal airways
Lead author Dr Jason Spence says:
"We expected different cells types to form, but their organisation into structures resembling human airways surprised us and is a very exciting result."
Embryonic stem cells
Proteins involved in lung development
Inhibitors of intestine development
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 are lacking several components of the native lung, including blood vessels, which are a critical component of gas exchange.
We hope to build on our initial findings to build increasingly complex mini-lungs by adding these components, eventually forming tiny organs able to perform functions related to breathing.