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An Experimental System to Study Mechanotransduction in Fetal Lung Cells
Published on: February 16, 2012
LGL1 modulates proliferation, apoptosis, and migration of human fetal lung fibroblasts
Hui Zhang1, Neil B Sweezey2, Feige Kaplan3
1Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada;
Insights
Late gestation lung 1 (LGL1) protein is crucial for lung development. Its deficiency impairs fibroblast function and epithelial cell migration, contributing to lung disease like bronchopulmonary dysplasia.
Area of Science:
- Pulmonary Biology and Medicine
- Developmental Biology
- Cellular and Molecular Medicine
Background:
- Perinatal lung development is characterized by rapid alveogenesis, forming new gas exchange units.
- Bronchopulmonary dysplasia (BPD), common in premature infants, results from arrested alveogenesis.
- Mesenchymal cells, specifically fibroblasts, regulate lung branching and alveogenesis via mesenchymal-epithelial interactions.
Purpose of the Study:
- To investigate the role of late gestation lung 1 (LGL1), a fibroblast-secreted protein, in lung development and mesenchymal-epithelial interactions.
- To explore LGL1's impact on fibroblast proliferation, migration, apoptosis, and wound healing.
- To understand LGL1's contribution to lung development processes relevant to bronchopulmonary dysplasia.
Main Methods:
- Developed a doxycycline-inducible RNA-mediated LGL1 knockdown cellular model using human fetal lung fibroblasts (MRC5(LGL1KD)).
- Assessed LGL1's effects on cell proliferation, migration, apoptosis (annexin V, caspase 3/7 activity), and wound healing.
- Analyzed gene expression changes in extracellular matrix and apoptosis pathways, and assessed 44/42MAPK phosphorylation.
Main Results:
- LGL1 knockdown in MRC5 cells suppressed cell growth and increased apoptosis.
- LGL1-conditioned medium enhanced migration of both fetal rat lung epithelial cells and human airway epithelial cells.
- LGL1 suppression led to downregulated extracellular matrix genes (MMP1, ColXVα1, ELASTIN) and upregulated pro-apoptosis genes (BAD, BAK, CASP2, TNFRSF1B), with inhibited 44/42MAPK phosphorylation.
Conclusions:
- LGL1 plays a significant role in fibroblast proliferation and migration, crucial for lung development.
- LGL1 promotes epithelial cell migration and is vital for effective wound healing in lung models.
- These findings highlight LGL1's importance in mesenchymal-epithelial signaling, impacting key processes in fetal lung development and potentially BPD pathogenesis.
Abstract:
Rapid growth and formation of new gas exchange units (alveogenesis) are hallmarks of the perinatal lung. Bronchopulmonary dysplasia (BPD), common in very premature infants, is characterized by premature arrest of alveogenesis. Mesenchymal cells (fibroblasts) regulate both lung branching and alveogenesis through mesenchymal-epithelial interactions. Temporal or spatial deficiency of late-gestation lung 1/cysteine-rich secretory protein LD2 (LGL1/CRISPLD2), expressed in and secreted by lung fibroblasts, can impair both lung branching and alveogenesis (LGL1 denotes late gestation lung 1 protein; LGL1 denotes the human gene; Lgl1 denotes the mouse/rat gene). Absence of Lgl1 is embryonic lethal. Lgl1 levels are dramatically reduced in oxygen toxicity rat models of BPD, and heterozygous Lgl1(+/-) mice exhibit features resembling human BPD. To explore the role of LGL1 in mesenchymal-epithelial interactions in developing lung, we developed a doxycycline (DOX)-inducible RNA-mediated LGL1 knockdown cellular model in human fetal lung fibroblasts (MRC5(LGL1KD)). We assessed the impact of LGL1 on cell proliferation, cell migration, apoptosis, and wound healing. DOX-induced MRC5(LGL1KD) suppressed cell growth and increased apoptosis of annexin V(+) staining cells and caspase 3/7 activity. LGL1-conditioned medium increased migration of fetal rat primary lung epithelial cells and human airway epithelial cells. Impaired healing by MRC5(LGL1KD) cells of a wound model was attenuated by addition of LGL1-conditioned medium. Suppression of LGL1 was associated with dysregulation of extracellular matrix genes (downregulated MMP1, ColXVα1, and ELASTIN) and proapoptosis genes (upregulated BAD, BAK, CASP2, and TNFRSF1B) and inhibition of 44/42MAPK phosphorylation. Our findings define a role for LGL1 in fibroblast expansion and migration, epithelial cell migration, and mesenchymal-epithelial signaling, key processes in fetal lung development.
