Repeated injury to respiratory tract stem cells could be


image: Biological aging of specific stem cells of tracheobronchial tissue (CST) and their trophic unit, the pseudostratified conductive epithelium of the airways. Each injury activates a subset of TSCs which proliferate and undergo terminal differentiation. Thus, each cycle of injury depletes the TSC pool and many injuries compromise epithelial regeneration. Over time, biological age exceeds chronological age and increases the risk of chronic lung disease.
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Credit: AlphaMed Press

Durham, North Carolina – Are prematurely aged or overworked stem cells a major contributor to chronic lung disease? The conclusions of a study that has just been published in STEM CELLS Translational medicine (MCTS) say it probably is.

The study determined that repeated damage to the epithelial tissue of the airways causes “biological aging” of the stem cells found there. “This premature aging of tracheobronchial stem cells (TSCs) may in turn contribute to chronic lung disease,” explained Susan D. Reynolds, Ph.D., of Nationwide Children’s Hospital in Columbus, Ohio, and co-principal investigator of the again study with Moumita Ghosh, Ph.D., University of Colorado School of Medicine, Anschutz Medical Campus.

Epithelial tissue is found throughout the body. Their functions include protection, secretion, absorption, excretion, filtration, diffusion and sensory reception. Previous studies have indicated that the ability of the epithelium to self-renew and differentiate declines over time, and that these changes decrease the ability to regenerate. This loss of function can cause the tissue-specific stem cell and its original tissue to be biologically older than its chronological age. (Chronological age is the number of years since birth, while biological age takes into account external factors that modify function.)

Previous studies have also shown that the biological age of lung cells is greater than their chronological age in at least two chronic lung diseases, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). “This work has identified accelerated aging as a novel process of lung disease; However, using this information to develop new therapies to treat patients requires a better understanding of chronological aging and the factors that increase biological age, ”said Dr. Reynolds. This was the objective of this last work.

Biological aging is associated with the shortening of telomeres. Telomeres, located at the ends of chromosomes, prevent the loss of genetic information during DNA replication. They shorten as cells divide in response to normal cell turnover or injury-induced cell death.

In an earlier study, Drs. Reynolds, Ghosh, and their team took issue with the idea that TSC maintains its function throughout an individual’s life. Instead, they suggested that the repeated proliferation of TSCs caused them to biologically age and lose their functional ability – a theory supported by the results of their study.

“In our latest study,” said Dr Ghosh, “we refined this concept by showing that injury activated only a fraction of the TSC mouse population and suggested that this process retained the mitotic potential of the sub. – inactive population. ” (Mitosis is the process by which cells divide and reproduce.)

After exposing mice to naphthalene – an aromatic hydrocarbon commonly used in mothballs and manufacturing – they used chromatin labeling and flow cytometry to determine that this injury activated a subset of TSC, which continued to proliferate after repair of the epithelium. A second exposure to naphthalene accelerated the proliferation of TSCs.

When the researchers examined why this was happening, they found that a new cohort of TSC had been activated and was responsible for epithelial regeneration. Thus, they concluded that partial activation of the TSC pool retained the mitotic potential of the remaining TSC.

Their analysis of mouse TSC also demonstrated that the majority of activated TSCs (96%) did not self-renew, but instead produced unipotential basal cells – the final progeny of TSC – and, therefore, were lost. from the TSC pool.

In summary, Dr Ghosh noted: “These mouse studies indicate that injury causes selective activation of the TSC pool and that activated TSCs are predisposed to further proliferation. He also demonstrated that the activated state of TSCs leads to terminal differentiation.

Next, the team analyzed the length of telomeres in human TSCs using bronchial and nasal cells donated by people with a rare disease of premature aging called congenital dyskeratosis (CD), which is caused by mutations in telomeres. . As a control, they also studied TSCs given by healthy people without the disorder.

As with mice, repeated proliferation in humans appeared to lead to terminal differentiation of TSCs and to a depleted TSC pool. “The frequency of TSCs was significantly decreased in DC patients compared to non-DC controls, long-lasting TSCs were not detected in DC patients, and TSCs from DC patients had short telomeres,” added Dr. Reynolds.

“Collectively, these data from mouse and human TSC studies indicate that many injury / repair cycles decrease the repair potential of the epithelium and that the magnitude of this decrease depends on the number of TSCs activated by each injury. . These studies identify the biological aging of TSC as a process that could lead to the development of chronic lung disease, ”the researchers concluded.

“This latest research adds more scientific knowledge to what we know about the development of chronic lung disease,” said Anthony Atala, MD, editor-in-chief of STEM CELLS Translational medicine and director of the Wake Forest Institute for Regenerative Medicine. “A better understanding of the biological aging of stem cells could one day lead to new treatments and therapies. “

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The full article, “Repeated Injury Promotes Tracheobronchial Tissue Stem Cell Attrition,” can be viewed at https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/sctm. 21-0032.

About Stem Cell Translational Medicine: STEM CELLS Translational Medicine (SCTM), co-edited by AlphaMed Press and Wiley, is a peer-reviewed monthly publication dedicated to the significant advancement of the clinical use of molecular and cellular biology of stem cells. By linking stem cell research and clinical trials, MCTS will help bring the applications of these critical investigations closer to accepted best practices. MCTS is the official partner journal of the Regenerative Medicine Foundation.

About the AlphaMed press: Founded in 1983, AlphaMed Press with offices in Durham, North Carolina, San Francisco, California and Belfast, Northern Ireland, publishes two other internationally renowned peer-reviewed journals: STEM CELLS® (http: //www.StemCells .com), celebrating its 39th year, is the world’s premier journal dedicated to this rapidly evolving field of research. The Oncologist® (http://www.TheOncologist.com), also a peer-reviewed monthly publication, entering its 26th year, is dedicated to community and hospital oncologists and physicians responsible for the care of cancer patients. All three journals are leading periodicals with globally recognized editorial boards dedicated to advancing knowledge and education in their targeted disciplines.

About Wiley: Wiley, a global company, helps people and organizations develop the skills and knowledge they need to be successful. Our online scientific, technical, medical and scholarly journals, combined with our digital learning, assessment and certification solutions, help universities, learned societies, businesses, governments and individuals to increase academic impact and professional in their work. For more than 200 years, we have provided consistent performance to our stakeholders. The company’s website can be accessed at http://www.wiley.com.

About the Foundation for Regenerative Medicine (RMF): The nonprofit Regenerative Medicine Foundation encourages strategic collaborations to accelerate the development of regenerative medicine to improve health and provide treatments. The RMF continues its mission by producing its flagship World Stem Cell Summit, honoring leaders through the Stem Cell and Regenerative Medicine Action Awards, and promoting educational initiatives.



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