Repeated Injury Promotes Tracheobronchial Tissue Stem Cell Attrition
Autor: | Saranga Wijeratne, Don Hayes, Moumita Ghosh, Alfahdah Alsudayri, Susan D. Reynolds, Barry R. Stripp, Zhang Hong Tan, Cynthia L Hill, Tendy Chiang, Gianni Carraro, John Mahoney, Scott W. Lallier |
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Rok vydání: | 2021 |
Předmět: |
Lung Diseases
Medicine (General) congenital hereditary and neonatal diseases and abnormalities Clone (cell biology) basal cell Biology chronic lung disease Flow cytometry Mice R5-920 Tissue‐specific Progenitor and Stem Cells Adult Stem Cells hemic and lymphatic diseases airway epithelial stem cell medicine Animals neoplasms Gene Cells Cultured QH573-671 Reinjuries medicine.diagnostic_test Stem Cells Cell Differentiation Cell Biology General Medicine medicine.disease Epithelium nervous system diseases Chromatin Telomere medicine.anatomical_structure biological aging embryonic structures Lung Stem Cells Cancer research Stem cell Cytology Dyskeratosis congenita Developmental Biology |
Zdroj: | Stem Cells Translational Medicine Stem Cells Translational Medicine, Vol 10, Iss 12, Pp 1696-1713 (2021) |
ISSN: | 2157-6580 2157-6564 |
Popis: | Chronic lung disease has been attributed to stem cell aging and/or exhaustion. We investigated these mechanisms using mouse and human tracheobronchial tissue‐specific stem cells (TSC). In mouse, chromatin labeling and flow cytometry demonstrated that naphthalene (NA) injury activated a subset of TSC. These activated TSC continued to proliferate after the epithelium was repaired and a clone study demonstrated that ~96% of activated TSC underwent terminal differentiation. Despite TSC attrition, epithelial repair after a second NA injury was normal. The second injury accelerated proliferation of previously activated TSC and a nucleotide‐label retention study indicated that the second injury recruited TSC that were quiescent during the first injury. These mouse studies indicate that (a) injury causes selective activation of the TSC pool; (b) activated TSC are predisposed to further proliferation; and (c) the activated state leads to terminal differentiation. In human TSC, repeated proliferation also led to terminal differentiation and depleted the TSC pool. A clone study identified long‐ and short‐lived TSC and showed that short‐lived TSC clones had significantly shorter telomeres than their long‐lived counterparts. The TSC pool was significantly depleted in dyskeratosis congenita donors, who harbor mutations in telomere biology genes. The remaining TSC had short telomeres and short lifespans. Collectively, the mouse and human studies support a model in which epithelial injury increases the biological age of the responding TSC. When applied to chronic lung disease, this model suggests that repeated injury accelerates the biological aging process resulting in abnormal repair and disease initiation. Biological aging of tracheobronchial tissue specific stem cells (TSC) and their trophic unit, the pseudostratified conducting airway epithelium. Each injury activates a subset of TSC which proliferate and undergo terminal differentiation. Thus, each injury cycle 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. |
Databáze: | OpenAIRE |
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