Silicosis is caused by the continuous inhalation of environmental
silica dust. The repetitive exposure of
silica induces airway epithelial cell injury, leads proliferative exhaustion of epithelial stem cells, ultimately results in the lung remodeling and the development of
silicosis. The B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) is a pivotal
transcription factor in stem cell self-renewal and proliferation of many tissues including the lung, but its role in the airway basal cell proliferation and differentiation during the pathogenesis of
silicosis in lung has yet been investigated. In this study, the function of Bmi1 in airway basal cell proliferation and differentiation in response to
silica challenge was investigated in lungs of
silicosis mice and primary human bronchial epithelia cells (HBECs) exposed to
silica dioxide (SiO2). Results showed a decreased expression of Bmi1
protein, epithelial basal cell markers Krt14 and Krt5, club cell marker
Clara cell secretory protein, and ciliated cell marker acetyl-α-
tubulin in
silicosis lungs, compared to healthy mice. In consistence, a persistent exposure of SiO2 reduced the capacity of cell proliferation and differentiation in HBECs, as ascertained by the reduction of differentiated epithelial cell markers and BMI1 expression, while an increased P21-positive senescent cell fraction. Moreover, an overexpression of BMI1 in HBECs reduced the SiO2-senescent cells, enhanced the potency of cell proliferation and differentiation, and increased capacity of airway epithelial regeneration in response to the persistent exposure of SiO2. These data suggest that Bmi1 is a key
transcription factor engaging in maintaining the self-renewal, proliferation and differentiation of epithelial stem cells in lung during the development of
silicosis disease.