TCF21 Deficiency Induces Fibroblast Apoptosis and Promotes Fibrotic Changes in the Human Lung Mesenchyme

Understanding processes driving alveolar niche regeneration in the human lung is essential for defining novel therapeutic strategies for lung diseases, such as chronic obstructive pulmonary disease (COPD). Using high-resolution DNA methylation profiling across COPD stages, we identified novel regulators of human lung regeneration, including TCF21[1]. TCF21 is a transcription factor regulating key fibroblast functions in many organs. Published mouse knockout data demonstrate that TCF21 is crucial for lung development and homeostasis of alveolar progenitors, however, its function in the human lung is largely unknown. Using qPCR and immunofluorescence, we demonstrate that TCF21 is upregulated in mild COPD (GOLD I) compared to controls and severe COPD, suggesting an interesting link to disease progression. TCF21 knockdown (KD) in primary human lung fibroblasts (HLF) triggered cell apoptosis and increased the expression of alpha-smooth muscle actin and collagen upon TGFβ1 stimulation, identifying the critical role of TCF21 in fibroblast survival, proliferation and fibroblast fate specification. RNA-sequencing of TCF21-KD HLF identified cell cycle, proliferation and apoptosis as core TCF21-regulated processes. Our findings position TCF21 as a novel pro-regenerative and anti-fibrotic factor within the lung, essential for maintaining fibroblast health and a potential target for novel COPD intervention. [1] Schwartz et al. 2023, EMBO