Human Airway Basal Stem Cells Created from Patients’ Cells

Scientists report that they have successfully created airway basal stem cells in vitro from induced pluripotent stem cells by reprogramming blood cells taken from patients.

Given that airway basal cells are defined as stem cells of the airways because they can regenerate the airway epithelium in response to injury, this study may help accelerate research on diseases impacting the airway, including COVID-19, influenza, asthma, and cystic fibrosis, according to the team led by researchers at the Center for Regenerative Medicine at Boston Medical Center and Boston University (CReM), in collaboration with the University of Texas Health Science Center at Houston (UTHealth).

These findings represent a critical first step towards airway regeneration, which will advance the field of regenerative medicine as it relates to airway and lung diseases, added the scientists.

The study, “Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells,” published in Cell Stem Cell, outlines how to generate and purify large quantities of airway basal stem cells using patient samples. This allows for the development of individual, disease-specific airway basal stem cells in a lab that can be used to develop disease models, which may ultimately lead to drug development and a platform in which targeted drug approaches can be tested.

The study’s findings and cells will be shared freely given the CReM’s “Open Source Biology” philosophy, or sharing of information and findings that will help advance science across the globe.

“The derivation of tissue-specific stem cells from human induced pluripotent stem cells (iPSCs) would have broad reaching implications for regenerative medicine. Here, we report the directed differentiation of human iPSCs into airway basal cells (iBCs), a population resembling the stem cell of the airway epithelium,” the investigators wrote.

“Using a dual fluorescent reporter system (NKX2-1 GFP;TP63 tdTomato), we track and purify these cells as they first emerge as developmentally immature NKX2-1 GFP+ lung progenitors and subsequently augment a TP63 program during proximal airway epithelial patterning. In response to primary basal cell medium, NKX2-1 GFP+/TP63 tdTomato+ cells display the molecular and functional phenotype of airway basal cells, including the capacity to self-renew or undergo multi-lineage differentiation in vitro and in tracheal xenografts in vivo.

“iBCs and their differentiated progeny model perturbations characterize acquired and genetic airway diseases, including the mucus metaplasia of asthma, chloride channel dysfunction of cystic fibrosis, and ciliary defects of primary ciliary dyskinesia.”

“Simply put, we have developed a way to reproduce patient-specific airway basal cells in the lab, with the ultimate goal of being able to regenerate the airway for patients with airway diseases,” said Finn Hawkins, MB, a pulmonologist and physician-scientist at Boston Medical Center, principal investigator in the CReM and the Pulmonary Center, and the study’s first author.

“These results could lead to a better understanding, and therefore treatments for, a variety of airway diseases,” noted Shingo Suzuki, PhD, co-first author and post-doctoral researcher at UTHealth. For example, cystic fibrosis is caused by a genetic mutation that is present in all of the airway cells.

“If we could make pluripotent stem cells using a sample from a patient who has cystic fibrosis, correct the mutation and replace the defective airway cells with corrected airway basal cells that are otherwise genetically identical, we might eventually be able to cure the disease, and other diseases in the future using this same technology,” added Hawkins.

The researchers first engineered induced pluripotent stem cells with a genetic sequence encoding a fluorescent protein that would allow them to visualize, track, and purify basal cells if present. Then, they turned to studies of the embryo and prior work in this field to determine how basal cells form as the lungs develop.

By manipulating induced pluripotent stem cells with a series of steps aimed to simulate what happens during lung development the researchers generated cells that were similar to human airway basal cells in terms of their appearance, the genes they expressed, and most importantly, their ability to both proliferate and form the other cell types of the airway.

The cells, termed ibasal cells, were able to regenerate an airway in vivo using a rodent trachea model.