Japanese researchers have generated lung cells directly from mouse tissue. These lung cells are called Alveolar Epithelial Type 2 (AT2 cells).
A team led by Professor Makoto Ishii from Nagoya University, alongside colleagues from Keio University, achieved this remarkable feat without using stem cell technology.
Using direct reprogramming, they have found a way to generate AT2-like cells much faster and more safely. Interestingly, this type of cell formation has “never been accomplished before.”
“In this study, we directly reprogrammed fibroblasts into AT2-like cells in mice. We now aim to explore the application of this technology to human cells, with the ultimate goal of developing a safe regenerative therapy using a patient’s fibroblasts,” Ishii stated.
Faster method than others
AT2 cells are like the lungs’ caretakers. They produce surfactant, which keeps air sacs open, and serve as progenitor cells to repair lung damage.
But for millions suffering from severe lung diseases like interstitial pneumonia and chronic obstructive pulmonary disease (COPD), these cell counts are reduced or don’t work properly.
This leaves patients with limited treatment options and a dire prognosis.
For years, the promise of regenerative medicine offered hope. While revolutionary, induced pluripotent stem cell (iPSC) technology takes about a month to generate AT2 cells.
But there are hurdles: it’s costly, and there’s a risk of tumor formation and immune rejection.
In this new development, researchers reprogrammed ordinary connective tissue cells called fibroblasts, taken from mice, directly into the desired lung cells, completely bypassing the need for stem cells.
“The advent of the induced pluripotent stem cell (iPSC) technology in 2006 has enabled the generation of AT2 cells in approximately one month, but this method is costly and carries risks of tumor formation and immune rejection,” said Ishii.
“To overcome these disadvantages, we focused on direct reprogramming instead. The direct reprogramming approach produces AT2-like cells in just 7 to 10 days, with lower tumor risk and potential for autologous use,” the author added.
How it was done
Researchers first screened 14 genes linked to lung development.
To identify the most efficient combination for reprogramming, they then measured the expression of surfactant protein-C (Sftpc), a marker for AT2 cells.
A potent mix of just four genes (Nkx2-1, Foxa1, Foxa2, and Gata6) was identified.
When these genes were introduced into mouse fibroblast culture, something incredible happened.
The fibroblasts were directly converted into iPULs (induced pulmonary epithelial-like cells)—functionally akin to native AT2 lung cells—in just 7 to 10 days.
This represents a major acceleration compared to other stem-cell-based methods, which take at least a month.
And these iPULs aren’t just a quick fix; they’re the real deal. When examined closely, they showed the characteristic internal structures of AT2 cells, called lamellar bodies. And their gene expression profiles were strikingly similar to healthy, native AT2 cells.
The ultimate test came when these iPULs were transplanted into mice with interstitial pneumonia.
The results were incredibly promising: the transplanted cells successfully integrated into the lung tissue after 42 days.
Moreover, some even transformed into AT1-like cells (Alveolar Epithelial Type 1), which play a key role in repairing lung damage.
This Japanese breakthrough creates new possibilities for treating severe lung diseases through safer and more personalized regenerative therapy.
The findings were published in the journal npj Regenerative Medicine.