The study, which appeared in the April 6 edition of Cell Stem Cell, was led by Dr. DarrellKotton, co-director of the Center for Regenerative Medicine (CReM) atBoston University and BMC and an attending physician in pulmonary, allergy andsleep medicine at BMC.
"The ability to generate a supply of progenitor cells withthe potential to differentiate into lung cells will be a huge boon to severalresearch fields," Dr. James Kiley, director of the Division of Lung Diseasesat the National Heart, Lung and Blood Institute (NHLBI), said in a pressrelease. "It lays the groundwork for studying the mechanisms and programming ofcells during lung development, which, in turn, will help develop newtreatments."
A progenitor is a cell that, like a stem cell, has thepotential to proliferate and self-differentiate into specific tissues.Progenitor cells from an embryo's gut tube, known as the endoderm, develop intothe lungs, thyroid, pancreas and gastrointestinal tract, among other organs.
Within the air sacs in human lungs, most cells are "finalfunctional forms," Kotton explains, and have lost the ability to divide andreplicate, which can limit the ability of the lung to regenerate.
"There's a brief window of time when the lung develops inthe 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 ifany of them are left over in the adult so we were trying to derive those cellsin culture, in vitro, from embryonicstem cells."
The development of thyroid and lung progenitors is closelylinked 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 onlytypes of endodermal cells that express the transcription factor NKX 2.1, and asthe researchers' goal was to derive cells that would activate that particulargene, it led to the derivation of both early thyroid and early lungprogenitors.
Researchers at CreM studied lung and thyroid development inthe developing embryo in order to learn about the sequence of development andrecreate the same sequences in embryonic stem cells in culture. The cells weremodified to include fluorescent tags that glowed at the moment lung or thyroidcells were generated from embryonic stem cells in culture. The researchers werethen able to differentiate the embryonic stem cells into gut tube endoderm andidentify growth factors that led to lung and thyroid growth. In the end, 160lung or thyroid progenitors could result from each stem cell, and thoseprogenitors could then be purified via the fluorescent tag, as it glowed onlywhen the cells had resolved into thyroid or lung cells.
"We succeeded in capturing a cell fate decision in culturedstem cells that is normally very transient during the earliest stages of lungand thyroid development," said Kotton in a press release. "Most importantly,our results emphasize that the precise inhibition of certain pathways atdefined stages is as important as the addition of pathway stimulators atdifferent developmental stages during lung and thyroid specification."
After the cells were derived, the researchers placed theminto a three-dimensional lung scaffold, in which the cells grew and replicatedto 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 peoplesuffering from lung disease.
"Patients with diseases that affect the lung epithelium…havea limited ability to repair or heal their epithelium," says Kotton. "And thelong-term goal of the project's to derive progenitor cells in culture thatmight be used in the distant future for therapeutic purposes."
The next step, according to Kotton, is to work with theprogenitor population and coax them into fully mature cells.
"We did this to a certain extent and built 3D lung tissuewith those cells and got them to differentiate, but I think the next step isnow to really optimize their maturation…to get them to really differentiate toa state that would resemble an adult lung epithelial cell, such an apneumocyte, an air sac cell that had the full function of any air sac cell inthe adult lung, that would really be the next important step," he says.
This study's research was done in collaboration with theMount Sinai School of Medicine, Massachusetts General Hospital and the VermontLung Center, and was funded by the NHLBI.
