An Aging Alveolar Lung Model in Microgravity - Abstract The accelerated aging seen in space provides a unique opportunity to model diseases, identify therapeutic targets, and test treatments more quickly than on Earth. Space conditions mimic age-related dysfunctions, allowing for faster progression and evaluation of therapies for a number of conditions. Here, we accordingly propose to use extracellular matrix-based scaffolds with interconnected spherical sacs, and human induced pluripotent stem cell-derived cells to develop an immunocompetent, vascularized, and ventilated three-dimensional (3D) model of the human alveolar lung as a truly biomimetic platform for understanding the interplays between pulmonary aging and aging-related disease conditions such as fibrosis, taking the advantage of the microgravity environment at the International Space Station-US National Laboratory. Our central hypothesis is that the use of biomimetic hydrogel matrices with interconnected spherical sacs with suitable stiffness, 3D co-culture of epithelial, endothelial, immune, and fibroblastic cells, in combination with a mechanically active microfluidic bioreactor, will enable simulating in vivo-like conditions under which different cell types would maintain their correct phenotypes and functions. Such a 3D alveolar lung model will for the first time enable faithful modeling of the healthy and fibrotic distal lung combined with microgravity in a human-based and (patho)physiologically relevant platform, providing a powerful tool for disease-modeling and testing new or existing therapeutics and as such envisaged to have significant and urgent implications in space medicine and more importantly, in benefiting life on Earth, and into the future for extended studies on lung diseases.
