LUMEN

Chronic Obstructive Pulmonary Disease (COPD) is a common respiratory disease mainly linked to prolonged tobacco use, with no curative treatment to date. It is often associated with emphysema, corresponding to destruction of the lung alveoli, which pathophysiology remains poorly understood. In this project, we aim at building a standardized 4D in vitro model of pulmonary alveoli (alveolospheres), by controlling the mechanical and chemical constraints governing cellular organization in vivo. We will use photopolymerized hydrogel microwells, thanks to a collaboration established for 2 years with the ALVEOLE© company, to seed alveolar epithelial cells (AEC) and human pulmonary mesenchymal cells and observe self-organization into spheroids. We will then expose cells to a cyclic mechanical stretch mimicking human breathing in order to observe the consequences on alveolospheres functionality. In addition, we will create a model of emphysema using several approaches. First, we will vary the size and stiffness of the microwells in order to mimic the mechanical stresses of emphysema. We will also expose the alveolospheres to cigarette smoke extract, thus reproducing the chemical aggression mainly involved in emphysema. By combining these approaches, we will be able to determine the role of the environment in the disease’s development. Finally, the respective role of each cell will be evaluated by performing heterologous cultures combining AECs from patients with emphysema and mesenchymal cells from patients without emphysema and vice versa. The pathophysiological pathways of emphysema will be evaluated for each condition: protease / anti-protease balance, apoptosis, senescence, inflammation. While controlling physical, chemical and biological parameters in our organoid culture, associated with dynamic stretching, we will obtain an innovative 4D pulmonary organoid model which can be used both in physiology and pathology.