A three-dimensional model of human lung development and disease from pluripotent stem cells

Abstract

Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modeling, drug discovery and regenerative medicine1. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants2, led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs3. Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis4,5, led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.

Human lung development: recent progress and new challenges

“…Another way to achieve relatively robust and consistent lung differentiation is by in vivo grafting into the mouse kidney capsule or lung epithelium (Chen et al, 2017; Huang et al, 2014; Miller et al, 2017). hPSC-derived lung organoids have also been cultured on scaffolds implanted into immune-compromised mice, resulting in improved airway epithelial, and mesenchymal, maturation compared with in vitro differentiation (Dye et al, 2015; Dye et al, 2016).…”

Take a deep breath and digest the material: organoids and biomaterials of the respiratory and digestive systems

“…[129] More recently, in a separate work the transplanted hPSC-derived branched lung organoids contained mature alveolar markers of AEI and AEII, but lacked the structure and shape of native airway and alveoli. [118] The alveolar structure is unique and does not form spontaneously in vitro. Biomaterial scaffolds provide an opportunity to direct the organization of cells into sac structures either in vitro or in vivo.…”

“…The retrieved tissue contained airway-specific markers lining the luminal branched structures, but lacked the cellular organization and cellular ratios of the native human lung airway. [118] Both the primary tissue-derived organoids and the hPSCderived branched lung organoids contained mature cell types, but overall, these tissues lacked a proper pseudostratified epithelium. [112,[119][120][121][122][123][124] On the other hand, scaffold-transplanted lung organoids derived from hPSCs formed a tube that was organized into a pseudostratified epithelium similar to the adult airway.…”

“…[4] Most recent studies have shown organoids that represent early stages of lung development can be injected with respiratory syncytial virus and the lung epithelium sloughs off, which is a known consequence of this virus. [118] The airway organoid model, derived from primary tissue, involves isolating the basal cell population from the primary tissue and culturing these cells in a threedimensional environment of Matrigel. Here, the basal cells form cyst structures that contain the basal cells along with other mature cell types of the airway.…”

Advances and Remaining Challenges in the Study of Influenza and Anthrax Infection in Lung Cell Culture

“…Optimizing this type of growth could pave the way in creating three-dimensional lung platforms on plastic scaffolds that mimic the branched architecture of the lung. Of note, a group at Columbia University [46] along with Japanese scientists [47] have recently culture 3D lung organoids from human-induced pluripotent stem cells (hiPSCs). While these platforms are primarily used to look at lung development and disease, there may be unique opportunities for use with pathogens.…”