Abstract
Research on acute and chronic lung diseases would greatly benefit from reproducible availability of alveolar epithelial cells (AEC). Primary alveolar epithelial cells can be derived from human lung tissue but the quality of these cells is highly donor dependent. Here, we demonstrated that culture of EpCAM+ cells derived from human induced pluripotent stem cells (hiPSC) at the physiological air-liquid interface (ALI) resulted in type 2 AEC-like cells (iAEC2) with alveolar characteristics. iAEC2 cells expressed native AEC2 markers (surfactant proteins and LPCAT-1) and contained lamellar bodies. ALI-iAEC2 were used to study alveolar repair over a period of 2 weeks following mechanical wounding of the cultures and the responses were compared with those obtained using primary AEC2 (pAEC2) isolated from resected lung tissue. Addition of the Wnt/β-catenin activator CHIR99021 reduced wound closure in the iAEC2 cultures but not pAEC2 cultures. This was accompanied by decreased surfactant protein expression and accumulation of podoplanin-positive cells at the wound edge. These results demonstrated the feasibility of studying alveolar repair using hiPSC-AEC2 cultured at the ALI and indicated that this model can be used in the future to study modulation of alveolar repair by (pharmaceutical) compounds.
Highlights
Research on acute and chronic lung diseases would greatly benefit from reproducible availability of alveolar epithelial cells (AEC)
We demonstrated that selection of EpCAM+ cells from differentiating human induced pluripotent stem cells (hiPSC) and followed by air-liquid interface (ALI) culture generates hiPSC-derived AEC2-like cells suitable for studying alveolar wound repair
When analysing wound closure at the ALI, we found that the Wnt-activator CHIR99021 delayed wound closure in both primary AEC2 (pAEC2) and investigate the feasibility of using hiPSC-derived AEC2 (iAEC2) cultures, with this effect being more pronounced and significant in iAEC2
Summary
Research on acute and chronic lung diseases would greatly benefit from reproducible availability of alveolar epithelial cells (AEC). Addition of the Wnt/β-catenin activator CHIR99021 reduced wound closure in the iAEC2 cultures but not pAEC2 cultures This was accompanied by decreased surfactant protein expression and accumulation of podoplanin-positive cells at the wound edge. The use of pAEC2 is further complicated by their inability to undergo passage in culture and tendency to differentiate spontaneously to terminally differentiated AEC1 confounding their use in lung repair studies[14] Since their initial description in 2007, human induced pluripotent stem cells (hiPSC) have been intensely used to study development and disease in vitro, and more recently for toxicity screening and drug discovery. The aim of the present study was to investigate the feasibility of using hiPSC-derived AEC2 (iAEC2) cultured at the air-liquid interface (ALI) as an in vitro model to study alveolar repair and to compare this model with that using pAEC2 isolated from lung tissue
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