If you tuned into the evening news on Monday night (at least here in Canada), you would have seen my PhD supervisor Janet Rossant, discussing a recent advancement in stem cell differentiation. Amy Wong, post-doctoral fellow in the Rossant lab, created a protocol for differentiating human pluripotent stem cells into mature airway epithelial cells. The protocol was published online in Nature Biotechnology.
Airway epithelial cells line the respiratory tract and protect the airway by keeping it moist. Mature airway epithelial cells express a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) that is located on the outer membrane of cells in organs including the lungs, pancreas and gut. The CFTR protein regulates ion transport across the cell membrane – to put it simply, it helps regulate the movement of water within an organ, allowing the production of normal mucus. Mucus protects tissues such as the lining of the respiratory tract from foreign bodies such as bacteria.
Cystic Fibrosis is a genetic disease that results from mutations in the CFTR gene where the CFTR protein is misdirected away from the cell membrane. Cystic Fibrosis patients have a build up of thick, sticky mucus in the lungs, which accumulates in the airways making it difficult to breathe. This build up of mucus also creates an inviting home for bacteria resulting in infection and subsequent lung damage. According to Cystic Fibrosis Canada, one in 3600 children born in Canada have Cystic Fibrosis and one person dies each week from the disease.
In the recently published protocol, skin cells obtained from a Cystic Fibrosis patient were reprogrammed into induced pluripotent stem cells (iPSCs) and then differentiated into airway epithelia. With the goal of drug screening in mind, SickKids researchers then treated the newly created cells with a previously identified small molecule called C18, a drug known to be capable of partially rescuing the Cystic Fibrosis CFTR defect. Upon treatment, the authors show that the cells correctly processes CFTR protein and that some CFTR can be detected at the cell membrane. While these results are exciting, additional optimization of the differentiation protocol is needed to decrease other contaminating cell types within the airway epithelium culture before scaling this up for drug screening. But the protocol is a significant step in finding a therapy for Cystic Fibrosis that targets the genetic mutation, rather than simply alleviating the symptoms, which is the only therapy currently available to patients.
This is not the first piece of evidence that drug screening in patient iPSC-derived cells is a feasible goal. Recently, Japanese researchers published a report in Science Translational Medicine in which they used motor neurons derived from Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s Disease) patient-derived iPSCs for the identification of a novel compound that is capable of rescuing the abnormal ALS motor neuron phenotype.
With more evidence being published on the potential utility of stem cells for drug screening, we can hope that the discovery of novel drug candidates won’t be too far behind.
Angela C. H. McDonald
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