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The proof is in the progenitors
BOSTON—Recent work by researchers at Boston University School of Medicine (BUSM) and Boston Medical Center (BMC), the principal teaching affiliate for BUSM, has led to the successful derivation of a population of pure lung and thyroid progenitor cells in vitro, ones that mimicked the developmental milestones of normal lung and thyroid tissue formation. The researchers were able to identify the necessary conditions and factors required for embryonic stem cells to differentiate into lung progenitor cells.
The study, which appeared in the April 6 edition of Cell Stem Cell, was led by Dr. Darrell Kotton, co-director of the Center for Regenerative Medicine (CReM) at Boston University and BMC and an attending physician in pulmonary, allergy and sleep medicine at BMC.
"The ability to generate a supply of progenitor cells with the potential to differentiate into lung cells will be a huge boon to several research fields," Dr. James Kiley, director of the Division of Lung Diseases at the National Heart, Lung and Blood Institute (NHLBI), said in a press release. "It lays the groundwork for studying the mechanisms and programming of cells during lung development, which, in turn, will help develop new treatments."
A progenitor is a cell that, like a stem cell, has the potential to proliferate and self-differentiate into specific tissues. Progenitor cells from an embryo's gut tube, known as the endoderm, develop into the lungs, thyroid, pancreas and gastrointestinal tract, among other organs.
Within the air sacs in human lungs, most cells are "final functional forms," Kotton explains, and have lost the ability to divide and replicate, which can limit the ability of the lung to regenerate.
"There's a brief window of time when the lung develops in the embryo, when a small set of progenitors give rise to the entire lung," Kotton notes, "and those are very special cells indeed. And we don't know if any of them are left over in the adult so we were trying to derive those cells in culture, in vitro, from embryonic stem cells."
The development of thyroid and lung progenitors is closely linked due to the fact that "the thyroid develops from the same germ layer (endoderm) as the lung," Kotton explains. The thyroid and the lung are the only types of endodermal cells that express the transcription factor NKX 2.1, and as the researchers' goal was to derive cells that would activate that particular gene, it led to the derivation of both early thyroid and early lung progenitors.
Researchers at CreM studied lung and thyroid development in the developing embryo in order to learn about the sequence of development and recreate the same sequences in embryonic stem cells in culture. The cells were modified to include fluorescent tags that glowed at the moment lung or thyroid cells were generated from embryonic stem cells in culture. The researchers were then able to differentiate the embryonic stem cells into gut tube endoderm and identify growth factors that led to lung and thyroid growth. In the end, 160 lung or thyroid progenitors could result from each stem cell, and those progenitors could then be purified via the fluorescent tag, as it glowed only when the cells had resolved into thyroid or lung cells.
"We succeeded in capturing a cell fate decision in cultured stem cells that is normally very transient during the earliest stages of lung and thyroid development," said Kotton in a press release. "Most importantly, our results emphasize that the precise inhibition of certain pathways at defined stages is as important as the addition of pathway stimulators at different developmental stages during lung and thyroid specification."
After the cells were derived, the researchers placed them into a three-dimensional lung scaffold, in which the cells grew and replicated to form two types of lung cells that usually coat the air sacs of the lungs. These results, Kotton says, could lead to a variety of therapies for people suffering from lung disease.
"Patients with diseases that affect the lung epithelium…have a limited ability to repair or heal their epithelium," says Kotton. "And the long-term goal of the project's to derive progenitor cells in culture that might be used in the distant future for therapeutic purposes."
The next step, according to Kotton, is to work with the progenitor population and coax them into fully mature cells.
"We did this to a certain extent and built 3D lung tissue with those cells and got them to differentiate, but I think the next step is now to really optimize their maturation…to get them to really differentiate to a state that would resemble an adult lung epithelial cell, such an a pneumocyte, an air sac cell that had the full function of any air sac cell in the adult lung, that would really be the next important step," he says.