Bioengineered lung microenvironments for the activation of homeostatic and regenerative pathways

Mesenchymal cells have a prominent role in the regulation of homeostasis and regeneration in the distal lung tissue. However, in diseases like chronic obstructive lung disease (COPD), where emphysema (i.e., enlargement of the alveoli or air sacs involved in oxygen exchange) is a major hallmark, these cells lose their support and the biochemical signaling from the extracellular matrix (ECM), which is irreversibly damaged. This leads to the impairment of the remaining healthy cells to drive the regeneration process. Thus, new alternatives to repair the ECM signaling and support are needed. In this project, we will make use of state-of-the-art tools to develop bioengineered ECM-like (bioECM) microenvironments based on an elastin-derived biomaterial. In addition, we will provide glycosaminoglycans able to bind specific growth factors necessary for lung homeostasis and regeneration. With this setup, we aim at triggering specific signaling pathways that promote a homeostatic or regenerative phenotype, which will be studied by RNA-sequencing (transcriptomics) followed by bioinformatic analysis of the results. This will allow us to have the whole picture in the interaction between the mesenchymal cells and the bioECM. These results will be confirmed by wet-lab methods involving the evaluation of protein expression through standard methods, like Western blot, immunohistochemistry, and ELISA measurements. Therefore, this project will set the grounds for further research towards the development of advanced ECM-mimetic microenvironments that enable the regeneration of lung tissue and the reversion of emphysema in COPD, which will be addressed in following steps.