Abstract
The lung is a radiosensitive organ, which imposes limits on the therapeutic dose in thoracic radiotherapy. Irradiated alveolar epithelial cells promote radiation-related pneumonitis and fibrosis. However, the role of lung stem cells (LSCs) in the development of radiation-induced lung injury is still unclear. In this study, we found that both LSCs and LSC-derived type II alveolar epithelial cells (AECII) can repair radiation-induced DNA double-strand breaks, but the irradiated LSCs underwent growth arrest and cell differentiation faster than the irradiated AECII cells. Moreover, radiation drove LSCs to fibrosis as shown with the elevated levels of markers for epithelial-mesenchymal transition and myofibroblast (α-smooth muscle actin (α-SMA)) differentiation in in vitro and ex vivo studies. Increased gene expressions of connective tissue growth factor and α-SMA were found in both irradiated LSCs and alveolar cells, suggesting that radiation could induce the fibrogenic differentiation of LSCs. Irradiated LSCs showed an increase in the expression of surfactant protein C (SP-C), the AECII cell marker, and α-SMA, and irradiated AECII cells expressed SP-C and α-SMA. These results indicated that radiation induced LSCs to differentiate into myofibroblasts and AECII cells; then, AECII cells differentiated further into either myofibroblasts or type I alveolar epithelial cells (AECI). In conclusion, our results revealed that LSCs are sensitive to radiation-induced cell damage and may be involved in radiation-induced lung fibrosis.
Highlights
Radiotherapy is a mainstay among treatments of thoracic malignancies such as lung cancer and esophageal cancer
When cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) growth medium, these isolated lung stem cells (LSCs) can proliferate and maintain the cobblestone epithelial morphology (Figure 1(a)). These isolated LSCs grown in MCDB-201 differentiation medium showed that the cell shape became flattened at day 7 and expressed surfactant protein C (SP-C, AECII marker) (Figure 1(a))
An extension of the incubation to 14 days led to further flattening and thinly enlargement of the cells that expressed podoplanin (T1α, AECI marker) (Figure 1(a)). These CD45−CD54+CD157+ LSCs display the capacity for self-renewal and differentiation into AECII cells and AECI cells in a sequential manner following induction signals in the culture medium [14]
Summary
Radiotherapy is a mainstay among treatments of thoracic malignancies such as lung cancer and esophageal cancer. The injured airway epithelial cells undergo apoptosis and secrete cytokines and growth factors that recruit immune cells and alter the microenvironment These inflammatory responses in the pneumonitis stage, which promote the maturation of fibroblasts and excess deposition of extracellular matrix, can subsequently develop into fibrosis [3, 4]. Recent studies suggest that terminally differentiated AECI cells undergo apoptosis for several months in response to ionizing radiation, which induces pulmonary pneumonitis [2, 5]. Previous studies have demonstrated that the Oct-4+ LSCs residing in the terminal bronchiolar region of the neonatal lungs are capable of being induced to differentiate into AECII and AECI cells [13]. Using in vitro cultured stem cells and differentiated cells of the lung may provide an easy-to-follow and less timeconsuming platform for drug screening and pave the way for tissue engineering and stem cell therapy in the radiation research
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