Comparison of KRT14 and KRT5 expression (markers for lung damage) in normal lung, IPF lung and ... [+]
Lungs that have sustained severe damage from diseases such as Covid-19 or Idiopathic Pulmonary Fibrosis (IPF) are characterized by the abnormal presence of basal cells in the tiny air sacs, known as alveoli, of the lungs. These misplaced basal cells interrupt the healing process, often leading to impaired lung function and even death.
Researchers at the University of California, San Francisco set out to learn why and how this happens. Released in Nature Cell Biology and co-led by Jaymin Kathiriya, Ph.D. and Chaoqun Wang, Ph.D., the report details a novel stem cell pathway in seriously injured lungs; specifically, the researchers discovered that human alveolar epithelial type 2 cells (hAEC2s) can turn into basal cells in response to signals sent by damaged and scarred mesenchyme tissue.
Our lungs are massively complex organs with many different components. The alveoli represent one part of this equation, helping to exchange oxygen and carbon dioxide between inhaled air and the bloodstream. Within the alveoli, AEC2 cells are responsible for maintenance and regeneration should anything bad happen. Basal cells, in turn, are mostly found in the conducting airways, a different section of the lung. Here they replace damaged cells and remodel the epithelium as needed in response to injury.
But the two don’t mix. At least, they shouldn’t.
So, it was to the great surprise of the researchers that both in vitro and in vivo models clearly showed hAEC2 transdifferentiation into KRT5+ basal cells—a rare process by which one cell type transforms into another.
For the in vivo model, Kathiriya et al. created a 3D organoid. Essentially, a tiny replica of the particular lung tissue in question. They did this by co-culturing hAEC2s with adult human lung mesenchyme. Mesenchyme tissue is responsible for the production of most of our body’s connective tissue, and, in the case of the lungs, is a critical determinant of their shape and size. By day 14, most of the organoid models contained KRT5+ basal cells.
The same result was reflected by an in vivo model, in which researchers transplanted human AEC2s into the damaged lungs of mice.
"The first time we saw hAEC2s differentiating into basal cells, it was so striking that we thought it was an error," said Peng. "But rigorous validation of this novel trajectory has provided enormous insight on how the lung remodels in response to severe injury, and a potential path to reverse the damage."
Further, when co-cultured with IPF-derived mesenchyme tissue, the rate of hACE2 to KRT5+ basal cell differentiation was noticeably accelerated. Kathiriya et al. also observed that adult human lung mesenchyme co-cultured with hACE2s underwent a dramatic shift in cellular identity, much more closely resembling IPF mesenchyme tissue than fresh adult human lung mesenchyme.
Comparative analysis of the hAEC2-derived basal cells with those present in IPF lungs revealed a very similar genetic expression. Although hAEC2-derived basal cells share certain foundational biomarkers with basal cells from a normal lung, they also over-express many of the same markers previously determined to be upregulated in damaged IPF lungs (Figure 2). As a whole, the hAEC2-derived basal cells had a lot more in common with the IPF lung basal cells than they did with those of the normal, healthy lung.
Wanting an even more detailed picture, the researchers performed a single-cell analysis of the cultured adult human lung mesenchyme. They found that BMP antagonists and transforming growth factor-β (TGF-β) ligands were significantly upregulated in the cultured mesenchyme. TGF-β plays a crucial role in cell proliferation and differentiation, so its upregulation would help describe the transdifferentiation of hAEC2s.
Along with this, Kathiriya et al. also described seeing intermediate cell types that acted as stepping stones in the transdifferentiation process. These intermediate cell types, as with the aforementioned biomarkers, are usually found in IPF lungs. Seeing the same intermediate cells arise in the researcher’s cultured organoid models suggests that they appear in response to alveolar damage, and are a key component of hAEC2 transdifferentiation.
This study shines light onto the intricate and aberrant process by which hAEC2 cells turn into basal cells in response to severe alveolar injuries, a transformation that changes the architecture of the lungs and can lead to further damage as well as impaired healing. Understanding the mechanisms at play is the first step towards developing a therapeutic intervention; with enough research, serious lung damage might become treatable and, at some point, maybe even reversible.
