Growing 3D miniature lungs from stem cells

Chuck Bednar for redOrbit.com – @BednarChuck

Researchers from the University of Michigan have cooked-up the perfect recipe for growing miniature, three-dimensional human lungs from stem cells, but you won’t find this recipe in a cookbook – it appears in the latest edition of the journal eLife.

Lead author Dr. Jason Spence, a professor at the UM Medical School in Ann Arbor, and colleagues from the Cincinnati Children’s Hospital Medical Center, the University of California, San Francisco (UCSF), Seattle Children’s Hospital and the University of Washington reported in their paper how they converted human pluripotent stem cells (hPSCs) into mini lungs.

Their work compliments with other recent research in the field (including building lung tissue from the scaffold of donated organs), the publishers of eLife said, and their method produces an organ that is more similar to the human lung than previous efforts because it can grow structures that closely resemble both the large proximal airways and the small distal airways.

The process

They took hPSCs (both embryonic and induced) and added a protein known as ActivinA, which is involved in lung development. They left the stem cells for four days, and during this period, a type of tissue known as endoderm formed. Found in early embryos, forms several internal organ types, including the lung and the liver.

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Next, they added a second protein – a growth factor called Noggin – and again left the growing tissues for four days. The endoderm was then induced to form 3D spherical structures known as the foregut spheroids. At this point, the scientists worked to make these structures expand and form into lung tissue by exposing the cells to proteins involved in lung development.

Once the spheroids were transferred into the protein mixture, they were allowed to incubate at room temperature for 10 minutes until the mixture solidified. They were treated with additional proteins every four days and transferred into a new protein mixture every 10 to 15 days.

The process is used to create lung organoids that should survive in culture for over 100 days and develop into well-organized structures containing cell types found in the lung, the study authors explained. The mini-lungs are essentially self-organizing, and once they are formed, they require no additional manipulation to generate three-dimensional tissues, they added.

Connective synergy

Unlike previous methods, which focused on forming the outer tissue of the lung (the epithelium), this new technique allows scientists to create connective tissues (mesenchyme). In addition, their method allows cells of the large proximal airways to form along with those of the small airways, which allows for a more complete study of the development of lung tissues and diseases.

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Alternatively, the researchers said that their method can be altered to have the foregut spheroids added to a lung scaffold from a human lung declared unsuitable for transplantation in order to make the organoids mature more quickly. Furthermore, stem cell lines from patients with genetic disorders that impact lung development can be produced (or mutations induced) in order to study how mutations affect cell differentiation, tissue organization, and tissue growth.

Since the structured were developed in a laboratory dish, however, they lack several key parts of an actual lung, including blood vessels. Dr. Spence and his colleagues hope to build upon their findings and create more complex mini-lungs by adding these missing components, with the goal of ultimately creating organoids that capable of performing functions related to respiration.

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