Scientists convert human embryonic stem cells into functional lung epithelial cells (green) (Photo: Sarah Xuelian Huang, CUMC)
While scientists have been able to successfully transform human stem cells into different types of cells such as nerve, retina and blood cells, creating working lung and airway cells proved to be a challenge.
"When an embryo develops, it first makes three layers of cells, or germ layers – ectoderm, which will become the skin and nervous system, mesoderm, which will become the heart, muscle, connective tissues, blood vessels, blood and kidney, and endoderm, which will become the intestine, liver, pancreas, stomach, esophagus, thyroid, thymus parathyroids, and lung," study leader Hans-Willem Snoeck tells Gizmag. "The endoderm forms last which is probably one reason why it is harder to specify from stem cells."
Studies that used the mouse embryo as a model couldn't demonstrate how the lung part of the endoderm formed. It wasn't possible for researchers to create lung cells until 2011, when Snoeck discovered a way to turn human embryonic stem cells into a particular type of cell, that were the precursors of lung cells.
"That was the first breakthrough that allowed this breakthrough," Snoeck explains. "We used what we knew from mouse development, and had to discover a few novel tricks."
This latest discovery identifies some new factors that allow human stem cells to complete their transformation into functional lung epithelial cells – these are the cells that cover the lung's surface. There are at least seven broad types of lung and airway lining cells which scientists will now be able to create, having functions ranging from maintaining the lung alveoli (small air sacs at the ends of airways that absorb oxygen from the air) to others that repair damage and injuries.
Cells within the lung such as those that make up the connective tissue and muscle, along with vascular cells and others belong to the mesoderm group, and require a different approach to generate. Snoeck's current breakthrough will open the way he says, to make "bioengineered lungs," that have little chance of rejection after transplantation, as they are made of the patient's own cells. The process is a complicated one.
"We'll need to reprogram adult cells (skin, blood …) to pluripotent stem cells similar to embryonic stem cells and convert them to lung cells, which is what our paper accomplished," Snoeck tells us. "The next step is to seed these onto donor lungs, or perhaps even pig lungs, from which all donor cells have been removed; the challenge is to remove all the cells, but leave the structure or scaffold intact."
Seeding the patient's own cells into a lung scaffold is extremely challenging, since it requires scaling up the generation of the cells which is an extremely expensive process. All the different types of airway and lung cells also have to go into the right place in the engineered lung.
"Some of these cells have beating cilia that remove all debris from the lungs and these have to beat in the right direction," continues Snoeck. "Our work is essential if we ever want to accomplish this, but a lot of engineering work is ahead."
The breakthrough is also expected to advance the study of lung diseases whose cause has been hard to identify. Being able to create models of these diseases and study them at a molecular level could, the researchers state, lead to strategies to screen for drugs to treat them.
"One example is idiopathic lung fibrosis, a disease where the aforementioned type II alveolar epithelial cells are believed to play a major role, but of which the pathogenesis or disease mechanism is not understood," Snoeck tells us. "This disease kills 20,000 people in the US yearly, and there is no curative treatment, except for lung transplantation, which carries a high mortality from transplant-related complications."
It could also shed light on human lung development, a process that's isn't well understood, and help in dealing with congenital diseases that affect the lung and airways such as tracheo-esophagal fistulas and tracheal atresia.
It may take anywhere from 5 to 10 years to come up with a bioengineered lung ready for transplantation, the team states, if all these challenges are met. Funding also poses a huge challenge. Snoeck is currently collaborating with the bioengineering department and with thoracic surgeons at Columbia to accomplish this goal. Their study was recently published in the journal Nature Biotechnology, and the university has filed a patent on the process.
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