Researchers at the University of Barcelona and the August Pi y Sunyer Biomedical Research Institute (IDIBAPS) have discovered that the IGFBP3 protein plays a crucial role in human lung development. This study, which used organoids from embryonic lungs, offers new insights into lung development and could lead to better prevention and treatment strategies for lung diseases, particularly those affecting newborns. The findings were published in the journal Stem Cell Research & Therapy, led by Alfons Navarro, a professor at the UB’s Faculty of Medicine and Health Sciences.
Understanding IGFBP3’s Role in Cell Development
IGFBP3 is a well-studied protein that impacts both disease processes, like cancer, and normal physiological functions. It regulates cell growth, differentiation, and survival. This new research highlights IGFBP3’s significance during the early stages of lung development. According to Melissa Acosta-Plasencia, a researcher at UB and the article’s first author, “This protein helps keep lung epithelial cells—those that line the lungs—in an undifferentiated state,” allowing them to develop into various cell types.
As the lungs mature, the levels of IGFBP3 must decrease to enable cell differentiation, which is essential for forming healthy lung tissue. Acosta-Plasencia noted, “As embryogenesis progresses, this protein needs to be silenced, indicating it is vital for maintaining lung stem cells.”
Interaction with miR-34a in Lung Development
The study also explored how IGFBP3 interacts with miR-34a, a microRNA that regulates gene expression. From the eighth week of lung development, miR-34a inhibits IGFBP3 production in the lung mesenchyme and epithelium, promoting the necessary cell differentiation during this developmental phase.
Organoids Simulate Lung Development
The research utilized organoids created from embryonic lungs between the eighth and twelfth weeks of human development. These organoids replicate lung structure at the molecular and cellular levels. Acosta-Plasencia explained, “In our study, we found that IGFBP3 gene expression was linked to embryonic lung progenitor cells. We required an in vitro model that could replicate this expression.”
These organoids, derived from pluripotent stem cells, mimic lung mucosa in 3D, allowing for interactive experiments. Researchers could activate cell differentiation processes or silence specific genes to observe their effects on lung development.
Using human embryos for this study provided “more accurate and biomedically relevant” results compared to animal models. The researchers noted, “While animal models are useful for understanding certain developmental aspects, there are significant differences in structure, function, and developmental timelines between species.”
Implications for Treating Lung Diseases and Cancer
Although further research is needed before clinical applications can be confirmed, the study’s results open new pathways for understanding respiratory diseases, particularly in premature infants. One such condition is pulmonary hypoplasia, a congenital defect where fetal lungs do not develop fully, leading to fewer and smaller alveoli. The researchers concluded, “Understanding how miR-34a regulates IGFBP3 expression could help develop targeted therapies that promote proper alveolar growth and improve lung function in affected newborns.”
In terms of cancer, IGFBP3 may also play a significant role in lung cancer, especially regarding cancer stem cells. The researchers found that higher levels of IGFBP3 in lung tumors are linked to poorer outcomes in the early stages of the disease. They suggested, “It would be worthwhile to explore whether modulating IGFBP3 could influence the differentiation of these cancer stem cells, potentially slowing their ability to migrate, invade, and grow metastatically.” They are continuing this line of research using organoids derived from lung cancer patients.
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