Guardians of the Lung: Role Of Stem Cells in Lung Repair

 

Undifferentiated cells that can divide continuously and proliferate to give rise to multiple cells of the same kind are called Stem cells. With advancements in the field of research and healthcare, Stem cells are being used for multiple purposes such as cell therapy, drug delivery, toxicology screening, etc., In this article, our topic of focus will be the role of Stem cells in lung tissue repair, in living mice. 

In the lung, alveolar type 2 (AT2) cells act as stem cells. They replenish both themselves as well as alveolar type 1 (AT1) cells, in the case of lung tissue damage. Following the detection of an injury site, the AT2 cells become motile. To observe the functioning of AT2 cells well, a mice model was produced by carrying out a cross between Sftpc-CreERT2 mice and mTmG mice. This Sftpc-CreERT2;mTmG mouse was operated upon to implant an optically transparent imaging window into its chest wall. Following a two-day recovery period, a lung injury was induced using Bleomycin (treatment), and PBS(control). Before the Bleomycin treatment, Tamoxifen was introduced into the tissue. This caused AT2 cells to express GFP (Green Fluorescence Protein), while the remaining cells that were labeled with tdTomato, appeared red.

The Intravital time-lapse imaging began on day 3 post-treatment. The mice were observed twice a day, for three days a week. During this time, approximately 45 percent of GFP-labeled cells showed motility in Bleomycin-treated mice. A plot of cell acceleration vs time identified a stop-and-start behavior of migration, rather than a continuous motion. These observations showed that motility is an early phase response to lung injury of some, but not all AT2 cells.

3-Dimensional rendering of individual fluorescently tagged cells was carried out, and their motility was tracked with respect to the surrounding alveolar septum as well as through alveolar pores, and alveolar boundaries. The results observed demonstrated that AT2 cells can migrate within, and beyond their specific alveolar regions, thus expanding their area of regeneration during early injury response.

The LCE-PHATE was used to observe the behavior of multiple individual cells and their response to injury over time. The LCE-PHATE converts static snaps of cellular behavior to low-dimensional embeddings of entire cellular trajectories. The time-lapse images show the entire trajectory followed by a single cell. This analysis showed that AT2 cell motility proceeds via a range of behaviors, rather than a single fixed trajectory.

Furthermore, the image analyses along with in-vivo and ex-vivo datasets, showed that the majority of AT2 cells increased in surface area and ellipticity while decreasing in sphericity, as compared to control (untreated, unaffected mice). However, the surface area and sphericity were poorly related to displacement. It was suggested that AT2 cells can respond to injury via multiple behaviourally distinct paths.

ArpC3 protein is an essential component for the migration of AT2 stem cells. When this crucial protein was depleted in AT2 stem cells, it was observed that there was an inhibition to their motility and capacity to migrate between alveoli. It was also noticed that it impaired proper alveolar repair.

 

Fig 1: A graphical abstract of the experiment and obtained results

Thus, through this study it was concluded that AT2 cells gain motility post-trauma, or injury. It was noted that there is a requirement for stem cell migration between alveolar units, and stem cell motility at high cellular resolution plays a major role in damage repair. 

REFERENCES:

1. Maurizio Chioccioli, Liu S, Magruder S, Tata A, Borriello L, McDonough JE, et al. Stem cell migration drives lung repair in living mice. Developmental cell. 2024 Apr 1;59(7):830-840.e4. https://doi.org/10.1016/j.devcel.2024.02.003

IMAGE SOURCE:

Cover Image: https://www.biospace.com/article/stem-cell-therapy-and-research-possibilities-and-challenges/

Fig 1: https://doi.org/10.1016/j.devcel.2024.02.003