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A team of researchers from Japan has developed a method for generating alveolar epithelial type 2 (AT2)-like cells from mouse embryonic fibroblasts without using stem cell technology. Remarkably, this process, which typically takes a month with conventional stem cell differentiation, has been reduced to just 7 to 10 days.
The new approach, published in npj Regenerative Medicine, may have significant implications for the treatment of respiratory diseases such as interstitial pneumonia and chronic obstructive pulmonary disease (COPD), which currently have limited treatment options. AT2 cells are critical for lung health, as they produce surfactant and help in alveolar repair. In severe lung diseases, these cells can be depleted or impaired, underscoring the potential therapeutic value of regenerating AT2 cells.
New approach to generating AT2-like cells
Induced pluripotent stem cell (iPSC)-based methods have enabled the creation of AT2 cells, but this process is expensive and time-consuming, inspiring researchers to search for faster alternatives.
“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,” explained Professor Makoto Ishii of Nagoya University Graduate School of Medicine.
“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,” Ishii said.
The researchers focused on reprogramming mouse fibroblasts to produce AT2-like cells, known as induced pulmonary epithelial-like cells (iPULs), in a significantly shorter period.
First, the researchers identified 14 candidate genes associated with lung development. By studying expression levels of the AT2 cell marker, surfactant protein-C (Sftpc), they were able to determine a combination of four genes with the highest reprogramming efficiency – Nkx2-1, Foxa1, Foxa2 and Gata6 – that were most effective in inducing AT2-like cells.
These genes were introduced into a 3D culture of mouse fibroblasts expressing green fluorescent protein (GFP) in response to Sftpc. Approximately 4% of the cells exhibited GFP positivity in 7 to 10 days, indicating the successful induction of iPULs.
Transplantation into mouse lungs
Following this, the researchers isolated the GFP-positive cells using flow cytometry and analyzed them. The purified iPULs displayed lamellar body-like structures, which are characteristic of normal AT2 cells. A transcriptomic analysis revealed that the gene expression profiles of the iPULs closely resembled those of native AT2 cells.
To test the functionality of these iPULs, the researchers transplanted them into mice with interstitial pneumonia. After 42 days, the transplanted cells successfully engrafted into the alveolar region. Notably, some of the cells differentiated into alveolar epithelial type 1 (AT1)-like cells, which are vital for lung tissue regeneration.
With the successful demonstration of the reprogramming of fibroblasts into AT2-like cells in mice, the researchers say that their next step will be to explore the potential for using this technology in human cells. The ultimate goal is to develop a safe regenerative therapy using a patient’s own fibroblasts, Ishii added.
Reference: Morita A, Ishii M, Asakura T, et al. Direct reprogramming of mouse fibroblasts into self-renewable alveolar epithelial-like cells. npj Regen Med. 2025;10(1):30. doi: 10.1038/s41536-025-00411-4
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