Effects of anti-tuberculosis drugs on the proliferation and differentiation of alveolar stem cells
Abstract
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), not only inflicts damage on lung epithelium but also poses a challenge to the regenerative capacity of the lung. Using lung organoid culture techniques, we assessed the effects of anti-Mtb drugs on the proliferation and differentiation of type II alveolar (AT2) cells. We found that rifampicin, pyrazinamide, ethambutol, and levofloxacin decreased the organoid-forming efficiency (OFE) of AT2 cells. Additionally, rifampicin and levofloxacin inhibited the size of organoids derived from AT2 cells. Isoniazid, ethambutol, and levofloxacin promoted type I alveolar (AT1) cell differentiation. Moxifloxacin considerably promoted the OFE and clone diameter while exerting minimal effects on AT1 cell differentiation. Furthermore, we performed metabolomics to elucidate the molecular mechanisms underlying lung epithelial stem cell regeneration. The differentially expressed metabolites were closely associated with energy metabolism, which is essential for cell proliferation and differentiation. Altogether, our data suggest that anti-Mtb drugs exhibit diverse and specific impacts on the growth and differentiation of AT2 cells. This may be directly related to the effect of drugs on the energy metabolism of alveolar stem cells, providing new insights and tools for the evaluation of anti-Mtb drugs.
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