In addition, the use of human embryos in this study has led to “much more accurate and biomedically relevant” results for understanding human lung development than those obtained with animal models. “Although animal models are useful for understanding certain aspects of development, there are key differences in structure, function and, above all, development time between species,” they add.

Therapeutic implications in respiratory pathologies and lung cancer

Although more studies are still needed to speak of clinical applications, the results of this work open new avenues to better understand respiratory diseases or conditions, especially in premature infants, such as pulmonary hypoplasia, a congenital anomaly of lung development in which the fetal lungs do not fully develop, resulting in a reduction in the number and size of the alveoli. “Understanding how miR-34a regulates IGFBP3 expression could facilitate the future development of targeted therapies that promote proper alveolar growth and improve lung function in neonates with this condition,” they conclude.

At the oncological level, IGFBP3 could also have a relevant role in lung cancer, especially in relation to cancer stem cells. “We have observed that elevated levels of IGFBP3 in lung tumour tissue correlate with a worse prognosis in early stages of the disease. Therefore, it would be interesting to investigate whether IGFBP3 modulation can influence the differentiation of these cancer stem cells, slowing down their capacity for migration, invasion and metastatic growth,” say the researchers, who are advancing in this line of research with organoids derived from lung cancer patients.

A key protein in the balance between pluripotency and cell differentiation

IGFBP3 is a molecule widely studied in both pathological processes — such as cancer — and physiological processes, and is involved in the regulation of cell proliferation, differentiation and survival. The new study has revealed a previously unknown aspect: the importance of this protein during human lung embryogenesis. As Melissa Acosta-Plasencia, researcher at the UB and first author of the article together with Joan J. Castellano, also a researcher, explains, “this protein helps to maintain lung epithelial cells — those that cover the inner surface of the lungs — in an undifferentiated state,” that is, it allows them to maintain their capacity to develop into different cell types.

As the lung develops, IGFBP3 expression must be reduced for cell differentiation to take place, a process necessary for proper lung tissue formation. “As embryogenesis progresses, this protein needs to be silenced, which tells us that it is key to maintain lung stem cells,” the researcher adds.

The study has also described the interaction between IGFBP3 and miR-34a, a microRNA-like molecule that plays a crucial role in the control of gene expression. From week 8 of lung development, this molecule acts by inhibiting IGFBP3 production in the lung mesenchyme and subsequently in the epithelium to facilitate the cell differentiation required at this stage of the development process.

Simulating lung development using organoids

The study has been carried out thanks to the generation and establishment of organoids derived from embryonic lungs between the 8^th and 12^th week of human development, which replicate this organ at the molecular and cellular level. “In our study, we observed that IGFBP3 gene expression was associated with embryonic lung progenitor cells. Therefore, we needed an in vitro model that could reproduce this expression,” says the researcher.

The organoids, based on pluripotent stem cells, reproduce in 3D a specific tissue, in this case the lung mucosa, which can be interacted with at different levels. “Thus, we have been able to activate cell differentiation processes or silence specific genes to evaluate their effects on lung development,” he explains.