Researchers develop new model of lung mesenchymal cells

(Boston) – Lung mesenchymal cells, a key component of the lung’s unique structure, also play an important role in recovery from disease and injury, but how their biology and diseases, such as pulmonary fibrosis, are affected. There is limited knowledge about what causes Although experimental models have helped identify several regulators of pulmonary mesenchymal behavior, it is unclear how pulmonary mesenchyme is identified during human development.

“Our work has implications for the study of pulmonary diseases such as pulmonary fibrosis and interstitial lung disease, which arise from the dysfunction of the part of the lung known as the mesenchyme. With very limited options, we hope our model system will help us understand what’s wrong with these diseases and provide new tools to screen for better drugs,” said the corresponding author. Darrell Cotton, M.D., David C. Seldin, M.D., Ph.D. Director of Center for Regenerative Medicine (CReM), BU/Boston Medical Center.

The researchers used an experimental model with an iPSC line carrying a pulmonary mesenchymal-specific fluorescent reporter. This means that cells that become pulmonary mesenchyme will be marked with green fluorescence. Using this model, they tested several growth factors and small molecules to stimulate pathways with known roles in lung development. They found that stimulating the Hedgehog signaling pathway with retinoic acid, which is known to play an important role in embryonic development, maximized the percentage of green fluorescent cells, indicating the potential presence of pulmonary mesenchyme. discovered. We then isolated those cells and compared their gene expression profiles with primary cells from embryonic lung in an experimental model to determine how similar these cells were to primary lung mesenchymal cells. Finally, they used a recombinant organoid system to test whether these cells could indeed function as lung mesenchyme.

“A key role of the developing lung mesenchyme in experimental models is its ability to interact with and signal adjacent epithelia. Our engineered cells are able to recapitulate some of these signaling interactions.” , suggesting that the cells have functional capacity,” explained lead author Dr. Andrea Alber, a postdoctoral fellow in Cotton’s lab.

According to the researchers, part of the study, combining genetically engineered lung mesenchymal cells with lung epithelial cells in a culture dish (the so-called “recombinant”) is live cells collected in a 3D culture gel. It is of particular interest because it yields certain organoids. This helps scientists understand how cells organize and communicate. “We are currently working on applying this kind of novel organoid model to better understand pulmonary fibrosis,” Alvar added.

These findings are published in the online journal Nature Communications.

This work was supported by the Swiss National Science Foundation (ABA P2ELP3_191217 and P500PB_206631) and the US National Institutes of Health (DNK U01HL134745, U01HL134766, U01HL152976, and R01HL095993; WS R01HL141352 and R01HL146541). ) was supported by , R56 DE028545-01 and R01HL158965-01 to LI). LI was also supported by the University of Buffalo (UB) Research Foundation Start-up Funds.Schematic was created at BioRender.com

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